Medicaments containing glycosidase inhibitors

Abstract

Pharmaceutical compositions and medicaments comprising O-GlcNAcase inhibitors are provided, as well as respective dosing regimens for administration to human patients for the treatment of various disorders, such as proteopathies, including tauopathies, synucleinopathies, and neurological disorders such as Alzheimer's disease.SOLUTION: A pharmaceutical composition comprising a compound of formula (I) and / or tautomers thereof for use in a method of treatment of a human subject, the method comprising repeatedly administering one or more unit dosage forms comprising the compound of formula (I) and / or tautomers thereof at a dose and a daily dosing frequency sufficient to maintain plasma concentrations of the compound of formula (I) and / or tautomers thereof in the range of about 45 to about 2000ng / mL at trough, wherein a dose of the compound of formula (I) and / or tautomers thereof administered at the daily dosing frequency is administered orally and ranges from about 150 to about 500mg.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions and medicaments containing O-GlcNAcase inhibitors, and The current trend is for neurological disorders such as tauopathies, synucleinopathies, and Alzheimer's disease. each for administration to a human patient for the treatment of various disorders, such as roteinopathy Regarding dosing regimens. [Background technology]

[0002] Background of the Invention A wide range of cellular proteins in the nucleus, cytoplasm, and mitochondria are bound by O-glycosidic bonds. The monosaccharide 2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetamido) This modification is generally O-linked N- It is called acetylglucosamine or O-GlcNAc. GlcNAc is attached to specific serine and threonine residues of numerous cytoplasmic / nucleocytoplasmic proteins. The enzyme that post-translationally attaches the glycan residue to the glycan is O-GlcNAc transferase (OGT or Another enzyme known as O-GlcNAcase is Post-translational modification is removed to release GlcNAc, and O-GlcNAc modification is then added to the protein. It is a dynamic event that occurs several times during the life of the

[0003] O-GlcNAc-modified proteins are involved in transcription, proteasomal degradation, and cell signaling. It regulates a wide range of important cellular functions, including but not limited to, cell proliferation. lcNAc is also found on many structural proteins. For example, it is found on neurofilament. protein, synapsin, synapsin-specific clathrin assembly protein AP-3, and It is found on many cytoskeletal proteins, including ankyrin G. It has been found that ATP is abundant in the brain and is a key factor in the development of tauopathy, Alzheimer's disease, and Alzheimer's disease. AD, synucleinopathy, Parkinson's disease, amyotrophic lateral sclerosis, and Proteins that are clearly involved in the pathogenesis of several diseases, including cancer (hereafter referred to as It is also found in quality.

[0004] For example, AD, as well as Down syndrome, progressive supranuclear palsy (PSP), Pick's disease, and cortical Basal ganglionic degeneration (CBD), argyrophilic granulomatosis (AGD), globular glial tauopathy (globu lar glial tauopathy (GGT), a gene linked to chromosome 17 Frontotemporal dementia with rheumatoid arthritis ia and parkinsonism linked to chromosome -17) (FTLD-17), and numerous related tauopathies, including Niemann-Pick disease type C. Well established that it is characterized, in part, by the development of neurofibrillary tangles (NFTs) NFTs are a histopathological feature of chronic traumatic encephalopathy, a consequence of traumatic brain injury. These NFTs are paired helical filaments (PHFs). Tau is an abnormal form of the cytoskeletal protein tau. Normally, tau is responsible for distributing proteins and nutrients within neurons. However, in AD patients, Tau becomes hyperphosphorylated, disrupting its normal function and forming PHFs, which ultimately aggregate. Six isoforms of tau are found in the human brain. In patients, all six isoforms of tau were found in NFTs, and all were significantly Tau in healthy brain tissue contains only 2-3 phosphate groups. Those found in the brains of AD patients contain an average of eight phosphate groups. The clear correspondence between brain NFT levels and dementia severity is a reflection of tau dysfunction in AD. This strongly supports a central role for tau. The exact cause of this hyperphosphorylation of tau remains unclear. Therefore, a) to elucidate the molecular physiological basis of tau hyperphosphorylation, and b) identify ways in which tau hyperphosphorylation can be suppressed, which may contribute to the development of tauopathies, synapses, and halting or even reversing the progression of cerebrovascular disease and Alzheimer's disease In anticipation of this, considerable efforts have been made. Several lines of evidence support the upregulation of multiple kinases. Recently, this has been suggested to be involved in the hyperphosphorylation of tau. Another fundamental understanding of hyperphosphorylation of is evolving.

[0005] In particular, tau phosphate levels are regulated by O-GlcNAc levels on tau. The presence of O-GlcNAc on tau has recently been shown to increase the O-GlcNAc level. This has prompted research into correlating the signal with the level of tau phosphorylation. The interest is in the presence of numerous proteins at amino acid residues that are also known to be phosphorylated. This observation stems from the observation that O-GlcNAc modification occurs on proteins. Consistent with this observation, increased phosphorylation levels led to decreased O-GlcNAc levels, and conversely , it has been found that increased O-GlcNAc levels correlate with decreased phosphorylation levels. This interrelationship between O-GlcNAc and phosphorylation has been termed the "yin-yang hypothesis," and Phosphatases and the enzyme OGT act to remove phosphate groups from proteins. This finding has received strong biochemical support from the recent discovery that the ribosomal proteins form functional complexes. Similar to phosphorylation, O-GlcNAc is removed and reintroduced several times during the life of a protein. The gene encoding O-GlcNAcase is a dynamic modification that can be associated with AD. It is suggested that the gene is located in the chromosome locus. The O-GlcNAc levels were significantly lower than those found in healthy human brains. Recently, O-GlcN of soluble tau protein from human brains affected by AD was identified. The Ac levels were significantly lower than those from healthy brains. These results suggest that HF ​​completely lacks O-GlcNAc modification. The molecular basis of silencing is unknown, but it may be due to increased activity of kinases and / or OG This may be due to a malfunction of one of the enzymes involved in lcNAc processing. Supporting the latter view, both PC-12 neuronal cells and mouse brain tissue sections showed In this study, nonselective N-acetylglucosamine was used to increase tau O-GlcNAc levels. When an α-dienidase inhibitor was used, a decrease in phosphorylation levels was observed. Furthermore, O-GlcNAc modification of tau disrupts the conformational properties of tau monomers. These results suggest that the ATP-dependent ATP synthesis is essential for the synthesis of ATP. For example, by inhibiting the action of O-GlcNAcase (OGA), AD patients can be improved. Maintaining healthy O-GlcNAc levels in individuals reduces tau hyperphosphorylation and and all of the associated effects of tau hyperphosphorylation, including NFT formation and downstream effects. However, the proper function of lysosomal β-hexosaminidase Therefore, blocking the action of O-GlcNAcase is a promising therapeutic approach for AD. A potential therapeutic intervention involves simultaneous inhibition of both lysosomal hexosaminidases A and B. would have to be avoided.

[0006] Known characteristics of the hexosamine biosynthetic pathway: O-GlcNAc transferase (OGT) Consistent with the enzymatic properties of O-GlcNAc and the interrelationship between O-GlcNAc and phosphorylation, It has been shown that reduced glucose availability leads to tau hyperphosphorylation. Gradual impairment of transport and metabolism of tau leads to a decrease in O-GlcNAc and tau (and This results in the hyperphosphorylation of O-GlcNAcase (and other proteins). have demonstrated the role of glucose in the brain of healthy individuals and patients with AD or related neurodegenerative diseases. This should compensate for age-related impairments in glucose metabolism.

[0007] These results suggest that dysfunction of the mechanisms regulating tau O-GlcNAc levels may contribute to NF-κB. These findings suggest that T-cell proliferation may be crucial in the development of T and associated neurodegeneration. Good support for blocking tau hyperphosphorylation as a useful intervention exists in human tau. When transgenic mice bearing the gene were treated with kinase inhibitors, they developed typical Studies have shown that patients do not develop motor impairments and otherwise show reduced levels of insoluble tau. These studies demonstrated the reduction of AD-like behavioral symptoms and the suppression of tau in mouse models of AD disease. These results show a clear correlation between the reduction in phosphorylation levels and the

[0008] O-GlcNAc modification may serve a general function in preventing harmful protein aggregation There is evidence that this is the case with tau protein and also with parkinsonism. Protein α-, a toxic aggregating protein associated with synucleinopathies, including Son's disease This has also been directly demonstrated for synuclein. Other aggregation events associated with amyotrophic lateral sclerosis The toxic proteins [Tar DNA-binding protein-43 (TDP-43) and superoxide dismutase (SDS)-dependent oxidodismutase I (SOD-I) and other aggregation proteins associated with frontotemporal lobar degeneration Proteins such as TDP-43 are known to contain O-GlcNAc modifications. The results show that the increase in O-GlcNAcylation with OGA inhibitors may prevent protein aggregation or The present invention is preferably directed to other protein misfolding-related diseases and the resulting The results suggest that the compound may be generally beneficial in certain diseases or conditions, i.e., proteinopathies. is doing.

[0009] Furthermore, increased levels of O-GlcNAc protein modification may contribute to the pathogenic effects of stress. There is also a large body of evidence that it provides protection.

[0010] Humans encode enzymes that cleave terminal β-N-acetyl-glucosamine residues from glycoconjugates. The first of these is the enzyme (protein)-3-O-( N-acetyl-D-glucosaminyl)-L-serine / threonine N-acetylglucosaminyl O-GlcNAcase encodes the hydroxylase (O-GlcNAcase). It is a member of glycoside hydrolase family 84. O-GlcNAcase , hydrolyzing O-GlcNAc at serine and threonine residues in post-translationally modified proteins Consistent with the presence of O-GlcNAc on numerous intracellular proteins, The enzyme O-GlcNAcase is involved in several diseases, including type II diabetes, AD, and cancer. O-GlcNAcase appears to play a role in pathogenesis. Although it appears that O-GlcNAc was isolated from serine and threonine residues in proteins, It took about 20 years for its biochemical role in cleaving ATP to be understood. Recently, O-GlcNAcase has been cloned and partially characterized, It has been suggested that it has additional activity as a stone acetyltransferase. Summary of the Invention

[0011] Overview of the invention The present invention relates to a compound of formula (I) [ka] and / or tautomers thereof (either in their respective free base forms or in their respective pharmaceutical compositions) Pharmaceutical compositions and medicaments containing the compound (in the form of a commercially available solvate or salt thereof), and The present invention further relates to a method for administering the compounds of the present invention to a human subject, and to a dosing regimen for their administration to a human subject. Compounds of formula (I) and / or tautomers thereof for use in a method of treating The method comprises the step of: and the unit dosage form of the compound of formula (I) is prepared in a suitable dosage and suitable amount as more particularly disclosed hereinafter. Repeated administration at a daily dosing frequency In another embodiment, the present invention provides a compound of formula (I) and / or One or more unit dosage forms containing tautomers may be used in combination with suitable tautomers as more specifically disclosed hereinafter. a pharmaceutical composition for the treatment of human subjects, including repeated administration at an appropriate dose and at an appropriate daily frequency; The present invention relates to the use of a compound of formula (I) and / or a tautomer thereof in the manufacture of a medicament. Compound (I) and its use as a glycosidase inhibitor are described, for example, in WO2016 / The object of the present invention is to provide a compound of formula (I) and / or Pharmaceuticals and pharmaceutical compositions containing tautomers, and methods for treating neurological disorders, such as tauopathies, syndromes, and the like Includes dosing regimens for the treatment of cerebrovascular disease and Alzheimer's disease. [Brief explanation of the drawings]

[0012] [Figure 1] Arithmetic mean plasma concentrations of Compound (I) following single oral administration of Compound (I) at seven dose levels (20 mg, 40 mg, 80 mg, 160 mg, 300 mg, 600 mg, and 1000 mg) in healthy male subjects—Part 1a. [Figure 2] Arithmetic mean plasma concentrations of Compound (I) on Day 12 after 12 days of BID administration of Compound (I) at 100 mg, 250 mg, and 500 mg dose levels in male and female elderly subjects—Part 2. [Figure 3] Arithmetic mean CSF concentrations of Compound (I) on Day 12 after 12 days of BID administration of Compound (I) at 100 mg, 250 mg, and 500 mg dose levels in male and female elderly subjects—Part 2. [Figure 4]Integral PET scan images of subject 1004: baseline, 6.9 hours after administration of 500 mg of Compound (I), and 8.1 hours after administration of 300 mg of Compound (I). [Figure 5] First reading: PK-RO (plasma concentration vs. receptor occupancy) analysis. Curve calculated according to: RO=100*Cp* / (Cp+EC50) (where RO=receptor occupancy, Cp=plasma concentration of compound (I), EC50=Cp corresponding to 50% RO). [Figure 6] Dissolution profile of capsules and tablets of Compound (I). DETAILED DESCRIPTION OF THE INVENTION

[0013] Details of the invention According to the present invention, medicaments and pharmaceutical compositions containing compounds of formula (I) and their administration to humans are provided. The dosage regimen for administration is a mediated Preventive or therapeutic treatment and / or monitoring of diseases mediated and / or proliferative Diseases that fall within the scope of the present invention include neurological diseases and neurodegenerative disorders. sexual disorders, diabetes, cancer, cardiovascular disease and stroke, more preferably neurodegenerative diseases, most preferably or one or more synucleinopathies and tauopathies, very preferably Alzheimer's disease These include dementia and glaucoma.

[0014] The compounds of formula (I) or medicaments or pharmaceutical compositions comprising formula (I) are used for the prevention or Other diseases that may be treated include diseases selected from one or more proteinopathies. Such proteinopathies include, preferably, tauopathies, Although not common, there are other diseases such as Alzheimer's disease (AD), corticobasal degeneration (CBD), and progressive dementia. PSP (progressive supranuclear palsy), chronic traumatic encephalopathy, or synucleinopathy (α-synuclein) (also called neuropathies), including but not limited to Parkinson's disease and multiple system atrophy is selected from the group comprising:

[0015] Another aspect of the present invention is directed to the treatment of neurodegenerative diseases, sleep disorders, such as insomnia, and psychosis. chronic conditions such as depression and schizophrenia, diabetes, cancer, cardiovascular disease and stroke, preferably or a method for treating a tauopathy, comprising administering to a subject a compound of formula (I) and / or its physiologically active agent. The medicaments or pharmaceutical compositions, including acceptable salts, may be administered in the dosage regimens disclosed herein. Therefore, the present invention relates to a method of treatment in which the compound is administered to a human in need of such treatment. A preferred method of administration is Oral administration is particularly preferred. Medicaments and pharmaceutical compositions according to the invention comprising compounds of formula (I) are It's nice.

[0016] The neurodegenerative disease or condition is more preferably selected from the group of: one or more of the following: Tauopathies, synucleinopathies, Alzheimer's disease (AD), and amyotrophic lateral sclerosis amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilia, behavior behavioral variant frontotem bvFTD, non-fluent and semantic variant primary progressive dementia Conductive aphasia (non-fluent and semantic variant pr natal progressive aphasia (NFV and SVPPA), Bluit disease, corticobasal degeneration (CBD), boxer - Dementia, dementia with Lewy bodies (DLB), diffuse neurofibrillary tangles with calcifications (dif fuse neurofibrillary tangles with calcif ication), Down syndrome, Familial British dementia, Familial Danish dementia, 1 Frontotemporal dementia with parkinsonism linked to chromosome 7 mporal dementia with parkinsonism linked to chromosome 17)(FTDP-17), Frontotemporal Lobar Degeneration (FTL D), glioma, ganglioneuroma, Gerstmann-Sträussler-Scheiker disease, bulbar globular glial tauopathy, Guad Loop parkinsonism, Hallervorden-Spatz disease (neurodegenerative type 1 with brain iron accumulation) ), lead encephalopathy, lipofuscinosis, meningioangiomatosis, multiple system atrophy (MSA), myotonic dysplasia Niemann-Pick disease (type C), Pallidopontonigral degeneration (Pallido-p onto-nigral degeneration), Parkinson's disease, Parkinson's Parkinsonism-Dementia Syndrome (PDD), Guam Parkinsonism-Dementia Syndrome, Pick's Disease (PiD), Brain Postinflammatory parkinsonism (PEP), prion disease [Creutzfeldt-Jakob disease (GJD)] , including variant Creutzfeldt-Jakob disease (vCJD)], fatal familial insomnia, Lew's disease, progressive supercortical gliosis gliosis), progressive supranuclear palsy (PSP), pure autonomic failure, PSP Richter Richardson syndrome, also known as Edwardson syndrome, subacute sclerosing panencephalitis, tangled Tangle-only dementia, tuberous sclerosis, Huntington's disease, or mild cognitive impairment disorder (MCI), chronic traumatic encephalopathy, primary progressive aphasia, progressive nonfluent aphasia, semantic Dementia, Steele-Richardson-Olszewski syndrome, epilepsy, chronic and Acute inflammation, such as Crohn's disease, neuroinflammation, subarachnoid hemorrhage (SAH), and multiple sclerosis (MS) ), progressive forms of MS, such as primary or secondary progressive MS, Friedreich's ataxia and adrenoleukodystrophy. Most preferred are one or more of tauopathy, PSP, and syphilis. Nucleinopathies, Parkinson's disease and Alzheimer's disease.

[0017] The compounds of formula (I) or pharmaceutically usable solvates, salts or tautomers thereof may be According to the dosage and administration regimen of the present invention, a human subject, e.g., a patient in need thereof, may benefit from It has been found in the present invention that the compound can be administered to

[0018] Throughout this specification, dosing regimens according to the present invention are directed to compounds of formula (I) and / or one or more units, including its tautomers or pharmaceutically acceptable solvates or salts thereof the dosage form is intended for repeated administration to a human subject at an appropriate dose and at an appropriate daily frequency; or includes.

[0019] Preferably, the administration regimen according to the present invention comprises a compound of formula (I) and / or a tautomer thereof. One or more unit dosage forms containing the isomer or a pharmaceutically acceptable solvate or salt thereof may be administered as appropriate. The present invention contemplates a method of treating human subjects, including repeated administration at an appropriate dose and at an appropriate daily frequency. Taste.

[0020] The present invention also relates to a method for treating retinal degenerative diseases, preferably glaucoma, age-related macular degeneration (AMD), retinal For the treatment and method of treating retinal degenerative diseases selected from pigmentary degeneration and diabetic retinopathy and the compounds of formula (I) and / or tautomers thereof and those disclosed herein. Regarding the use of dosing regimens.

[0021] The present invention also relates to the treatment of inflammatory bowel diseases, preferably colitis, e.g., ulcerative colitis, and clostridium erythropoietin. and a compound of formula (I) for the treatment and method of treating an inflammatory bowel disease selected from the group consisting of inflammatory bowel disease and inflammatory bowel disease. and / or its tautomers and the use of the dosing regimens disclosed herein. do.

[0022] Disclosures of medical uses of the compound itself may be omitted if the compound is included in a pharmaceutical composition or medicament. as well as the use of the compound when it is incorporated into the pharmaceutical compositions disclosed herein. as well as the use of the compound when used in a therapeutic method or administration regimen The same is true in reverse, e.g., in pharmaceuticals. Use of the compound in a composition, medicament, or method of treatment involving administration of the compound, or administration Disclosure of the use of a compound as part of a therapeutic regimen is not intended to be construed as a medical use of the compound itself. It should be understood that this applies.

[0023] As used herein, the term "about" refers to a particular value, e.g., an endpoint of a range. If a value is specifically listed, then in addition to the specifically listed value itself, values ​​above and below that specifically listed value Certain variations are encompassed and disclosed. Such variations may arise, for example, from normal measurement variability. The term "about" refers to the exact stated value itself as well as to a variation above and below the particular value stated. Ranges should be understood as encompassing and disclosing, and the variability may vary, for example, within a particular column. The term "about" encompasses and discloses a variability of ±5.0%. The term "about" encompasses and discloses a variability of ±4.5%. The term "about" encompasses and discloses a variability of ±4.0%. The term "about" encompasses and discloses a variability of ±3.5%. The term "about" encompasses and discloses a variability of ±3.0%. The term "about" encompasses and discloses a variability of ±2.5%. The term "about" encompasses and discloses a variability of ±2.0%. The term "about" encompasses and discloses a variability of ±1.5%. The term "about" encompasses and discloses a variability of ±1.0%. The term "about" encompasses and discloses a variability of ±0.5%. Unless otherwise specified, the word "about" precedes the first endpoint of a numerical range. , if not listed before the second endpoint of the range, this term and disclosure The variability implied by this is the difference between the first endpoint of the range and the second endpoint of the range. For example, the enumerated range "about X to Y" is about X~ about It is interpreted as "Y" Also, when the term "about" is applied to both the upper and lower limits of a range, It should be understood that different degrees of variability may apply to the upper and lower limits of the same range. All such possible degrees of variability are within the scope of the present disclosure. For example, In the range "about X to about Y," the present application specifically provides that the lower limit X has an acceptable range of 1.5% of the stated value. While it varies within a range, it discloses a range where the upper limit varies within a tolerance of 2% of the stated value. Of course, this is merely an example, and all combinations of the above permissible ranges are included within the disclosure of this application. It is understood that

[0024] The term "human subject" preferably refers to a patient with a disease or at risk of developing a disease. is taken to mean a human subject in which the disease is preferably More preferably, the term "human subject" refers to a disease selected from the diseases mentioned above. A condition selected from the group consisting of neurological or neurodegenerative diseases, diabetes, cancer, cardiovascular disease, and stroke "disorder" refers to a human subject having a condition or at high risk of suffering from said disorder or disease. This is interpreted as:

[0025] Preferably, the patient is suffering from a neurological disorder or neurodegenerative disease, such as PSP or Alzheimer's disease. With respect to risk of developing a neurological disorder or neurodegeneration, in some embodiments, the subject is at risk of developing a neurological disorder or neurodegeneration. be identifiable as having an increased risk of developing a sexually transmitted disease, such as PSP, or The individual may be identified as having a neurological disorder or neurodegenerative disease, e.g., Specifically, for example, in the gene encoding the microtubule-associated protein tau (MAPT), Genetic changes [e.g., any of the inversion polymorphisms in the MAPT gene, any of the haplotype-specific polymorphisms in the MAPT mutation (A152T), or splicing of exon 10 in the MAPT gene Mutations that enhance signaling (e.g., Hoglinger et al., Nature Genet .43:699-705, 2011 and Hinz et al., Cold Spring Har b. Perspective Biol. Non-limiting examples of genetic alterations in the gene encoding MAPT include S28 MAPT, containing one or more point mutations: 5R, L284R, P301L, and G303V These include mutations that result in the production of proteins that cause neurological or neurodegenerative disorders, e.g. can be used to identify subjects as having an increased risk of developing PSP or identifying a subject as having a neurological disorder or neurodegenerative disease, e.g., PSP. Additional specific sequences in the gene encoding the MAPT protein can be used to Genetic mutations are described, for example, in Boxer et al., Lancet 16:552-563, 20 17.

[0026] In some embodiments, the subject has a gene encoding presenilin 1 (PSEN1) or 2 (PSEN2). Genetic alterations in the SEN2 or β-amyloid precursor protein (APP) genes or by the presence of the ε4 allele of the apolipoprotein E (APOE) gene. by having relatives with these changes in their genes thus, an increased risk of developing neurological disorders or neurodegenerative diseases, such as Alzheimer's disease can be identified as having

[0027] In some embodiments, the subject has a condition characterized by, for example, at least in part, tau protein Detecting deposits (e.g., 4-repeat tau protein deposits) in the midbrain and / or supraspinal cortex Detecting peduncular atrophy [e.g., as described herein or known in the art] Any of the imaging techniques, such as magnetic resonance imaging (MRI) or positive using electron emission tomography (PET) scans], and / or prior Detecting hypometabolism in the temporal lobe, caudate nucleus, and / or thalamus (e.g., as described herein) or known in the art, e.g., MRI, CT scan, or PET scan) to determine whether there is neurological or neurological damage. Identifiable as having an increased risk of developing a degenerative disease, such as PSP or identifiable as having a neurological disorder or neurodegenerative disease, such as PSP. do.

[0028] In some embodiments, the subject is, for example, at least in part, a patient with a The presence or absence of one or more biomarkers (e.g., compared to levels in healthy control subjects) ) By detecting its elevated level, it is possible to diagnose neurological disorders or neurodegenerative diseases, such as PS identifiable as having an increased risk of developing P or neurological disorders or can be identified as having a neurodegenerative disease, such as PSP.

[0029] In some embodiments, the subject is a sports participant (e.g., boxing, American Having suffered a concussion / brain injury as a result of football, military blast injury, or traffic accident identified as having an increased risk of developing a neurological disorder or neurodegenerative disease It can be determined.

[0030] In some embodiments, the subject is over 65 years of age. may be identified as having an increased risk of developing a neurological disorder or neurodegenerative disease do.

[0031] In some embodiments, the subject is diagnosed with a condition, e.g., heart disease, stroke, hypercholesterolemia, Predisposing conditions such as obesity, high blood pressure and diabetes can increase the risk of neuropathy or dementia. They may be identified as having an increased risk of developing degenerative diseases.

[0032] The term "solvates" of a compound is understood to mean adducts of inert solvent molecules onto the compound. The solvates are also known as monohydrates, which are formed by their mutual attractive forces. The present invention also relates to a solution of a salt of the compound according to the present invention. Includes solvents.

[0033] The compounds of formula (I) and / or their tautomers are preferably in their non-racemic form. Used, i.e., enantiomerically pure compounds, or enantiomers It is most preferably used as an enantiomerically enriched mixture of the enantiomers. An isomerically enriched mixture is one that has an enantiomeric excess of greater than 95% or greater than 98%. By "tautomer" is meant compounds of formula (I) and / or tautomers thereof having a tautomeric form.

[0034] Desirably, the compositions of the present invention contain the corresponding isomers, e.g., compounds of formula (I) and / or is substantially free of its tautomeric enantiomer. The pharmaceutical composition is substantially free of isomers and is / are a compound of formula (I) and / or The tautomer is at least 90% by weight, or the corresponding isomer is at least 10% by weight. In another embodiment, it means that the compound is substantially free of the corresponding isomer. Alternatively, the pharmaceutical composition may contain a small amount of the compound of formula (I) and / or its tautomer. This means that the content of the corresponding isomer is 95% by weight or less, or that the content of the corresponding isomer is 5% by weight or less. In yet another embodiment, the pharmaceutical composition is substantially free of the corresponding isomer. In the present invention, the compound of formula (I) and / or its tautomer is at least 99% by weight. or the corresponding isomer is 1% by weight or less.

[0035] The compounds of formula (I) and / or their tautomers may be used in their final non-salt form. On the other hand, the present invention provides Compound (I) and / or its derivatives in the form of a pharmaceutically acceptable acid addition salt. or tautomers thereof, which forms are intended to render the respective compounds pharmaceutically acceptable. These can be formed by treatment with a variety of organic and inorganic acids, including, for example: Hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, etc. and their corresponding salts, such as sulfates, nitrates or phosphates, and alkyl- and monoarylsulfonates, e.g., methanesulfonate, ethanesulfonate, Sulfonates, toluenesulfonates and benzenesulfonates, and other organic acids and its corresponding salts, such as carbonate, acetate, trifluoroacetate, tartrate Glutamate, maleate, succinate, citrate, benzoate, salicylate, ascorbate Thus, the pharmaceutically acceptable acid addition salts of the compounds according to the present invention include the following: Contains: acetate, adipate, alginate, alginate, asparagine Acid salts, benzoates, benzenesulfonates (besylates), bisulfates, bisulfites, bromides Butyrate, Camphorate, Camphorsulfonate, Caprate, Caprylate, Chloride, Chloride Benzoates, citrates, cyclamates, cinnamates, cyclopentanepropionates , digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate Fonates, formates, glycolates, fumarates, galacterates te) (derived from mucic acid), galacturonate, glucoheptanoate, gluconate, glutarate Salt, glycerol phosphate, hemisuccinate, hemisulfate, heptanoate, hexane acid salt, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate Phosphate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate Salt, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methacrylate methyl benzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitric acid Salt, oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate , 3-phenylpropionate, phosphate, phosphonate, phthalate. The list is not intended to be limiting.

[0036] Hydrochloric acid, maleic acid, tartaric acid, sulfuric acid or p-toluenesulfonic acid with a compound of formula (I) Particularly preferred is the acid addition salt with the following formula (I): The hydrochloride salt of formula (I) is most preferred.

[0037] Another aspect of the invention is a compound of formula (I) for administration to a human to inhibit glycosidases, Medicaments and pharmaceutical compositions containing compounds of formula (I) and / or their tautomers and Such uses may be therapeutic or non-therapeutic in nature. The term "inhibit" refers to the inhibition of a target glycoprotein in a manner that allows for recognition, binding, and blocking. The inhibition of glycosidase activity is based on the action of certain compounds of the present invention that can interact with glycosidases. Any reduction is meant.

[0038] In a preferred embodiment of the present invention, the glycosidase is a glycoside hydrolase, more preferably a More preferably, a Family 84 glycoside hydrolase, most preferably a (protein)- 3-O-(N-acetyl-D-glucosaminyl)-L-serine / threonine N-acetyl O-Glucosaminyl hydrolase (O-GlcNAcase), very preferably mammalian O- The compound of formula (I) according to the present invention contains O-GlcNAcase. and thereby selectively binds to, for example, 2-acetamido-2-deoxy-β-D- Selectively inhibits glucopyranoside (O-GlcNAc) cleavage while inhibiting lysosomal β It is particularly preferred that the compound does not substantially inhibit hexosaminidase.

[0039] As described herein, glycosidase signaling pathways are involved in a variety of diseases, Preferably, it is associated with neurodegenerative diseases, diabetes, cancer, cardiovascular disease and stroke. Thus, the compounds according to the present invention inhibit the signal transduction pathway by interacting with one or more of the signal transduction pathways. These compounds are useful in the prevention and / or treatment of diseases that depend on the nucleotide signaling pathway. The present invention relates to a method for treating a cancer cell that is mutated orally, in a manner that inhibits the signal transduction pathways described herein, preferably OGA-mediated signal transduction pathways. Therapeutic and Non-therapeutic Uses of Compounds According to the Invention as Inhibitors of Neural Transmission Regarding.

[0040] Another aspect of the present invention is a compound of formula (I) and / or its tautomers and / or or a pharmaceutically acceptable salt or solvate thereof. A "medicine" in this context is a drug that reduces or eliminates pathogenic changes in the patient's overall condition or the condition of a specific area of ​​the organism. In a manner that is temporarily established, the prevention, treatment, and progress of patients with diseases related to OGA activity are The compound of formula (I) or a formulation thereof (e.g., A drug is any substance in the field of medicine, including, for example, a pharmaceutical composition or pharmaceutical preparation. Preferably, the active ingredient is prepared by a non-chemical method, for example by mixing the active ingredient with at least one solid, soluble or non-soluble component. By combining with a solid and / or semi-fluid carrier or excipient, and optionally It is prepared in a suitable dosage form by combining it with one or more other active substances.

[0041] In the sense of the present invention, an "adjuvant" is an adjuvant administered simultaneously, contemporaneously or sequentially. When administered, the compounds enable, enhance, or modify a specific response to the active ingredients of the present invention. Known adjuvants for injection solutions include, for example, aluminum aluminum compositions, such as aluminum hydroxide or aluminum phosphate, saponins, e.g. QS21, muramyl dipeptide or muramyl tripeptide, proteins, e.g., gamma -Interferon or TNF, M59, squalene or polyols.

[0042] In particular, the present invention relates to a method for administering a medicament or pharmaceutical composition according to the present invention to a human patient in need thereof. The administration regimen is for treating tauopathies, such as PSP, Particularly suitable for the treatment of neurological or neurodegenerative diseases, including Alzheimer's disease or dementia .

[0043] Regarding O-GlcNAcase inhibition as a therapeutic mechanism, Occupancy and / or inhibition of the enzyme or target is preferred. Maintaining sufficient O-GlcNAcase inhibitor concentrations during treatment is essential for the recovery of enzyme activity. is a key determining factor in ensuring that

[0044] Therefore, preferably, the therapeutic activity of the compounds of formula (I) and / or their tautomers is The efficacy is at least about 35% at trough, preferably at least about 40% or 50%, more preferably at least about 60% or 70% at the trough , most preferably at least about 80%, 90%, or 95% target occupancy in the trough. Guaranteed rate.

[0045] In one embodiment, the target occupancy in the trough ranges from about 40% to about 95%. In another embodiment, the target occupancy in the trough is about 60% to about 95%. In another embodiment, the target occupancy in the trough is at least about 70 In another embodiment, the target occupancy in the trough is at least about 95%. At most, it is about 80% to 95%.

[0046] A therapeutically effective amount of a compound of formula (I) and / or its tautomer is preferably a compound of formula ( I) the average target occupancy over 24 hours during treatment with a drug or formulation containing the compound is low at least about 70%, preferably at least about 80% or 85%, more preferably at least Preferably, the solubility is at least about 90%, and most preferably at least about 95%.

[0047] In one embodiment, a compound of formula (I) and / or a tautomer thereof or within 24 hours during treatment with a medicament or formulation containing a pharmaceutically acceptable solvate or salt of The average target occupancy ranges from about 80% to about 95%. is a compound of formula (I) and / or a tautomer thereof or a pharmaceutically acceptable solvent thereof Range of mean target occupancy over 24 hours during treatment with a drug or formulation containing a solvate or salt In another embodiment, the range is from about 85% to about 98%. and / or its tautomers or pharmaceutically acceptable solvates or salts thereof The average target occupancy over 24 hours during treatment with the formulation ranged from approximately 88% to approximately 99%. be.

[0048] Preferably, the therapeutically effective amount is a compound of formula (I) and / or a tautomer thereof or During treatment with a drug or formulation containing a pharmaceutically acceptable solvate or salt thereof, and at least about 70% target occupancy in the brain over 24 hours. Guarantees an average target occupancy of 80%.

[0049] Preferably, the therapeutically effective amount is a compound of formula (I) and / or a tautomer thereof or During treatment with a drug or formulation containing a pharmaceutically acceptable solvate or salt thereof, and at least about 80% target occupancy in the brain over 24 hours. Guaranteed average target occupancy of 90%.

[0050] In preferred embodiments, target occupancy is a disorder characterized by a neurological or neurodegenerative disease, diabetes, cancer, or the like. , cardiovascular disease and stroke, preferably neurological or neurodegenerative diseases, including PSP. A clinical effect resulting in a reduction or amelioration of the progression of signs and symptoms of the disease. In embodiments, administration regimens comprising compounds of formula (I) and / or tautomers thereof The study is aimed at treating neurological disorders or neurodegenerative diseases, such as PSP, particularly brain tau burden, global and regional Reduce or improve the progression of brain atrophy, decreased ability to perform daily activities, and signs and symptoms of cognitive impairment Furthermore, administration regimens containing compounds of formula (I) and / or their tautomers may be bioavailable. Omarker results improve overall clinical condition and quality of life.

[0051] In one embodiment, a dosage form comprising a compound of formula (I) and / or a tautomer thereof is In one embodiment, the administration regimen reduces neuroinflammation. In another embodiment, a dosing regimen comprising: In this context, administration regimens comprising compounds of formula (I) and / or tautomers thereof may be used to treat neurodegenerative disorders. In another embodiment, the compounds of formula (I) and / or their analogs are Dosage regimens containing the variants reduce brain atrophy or degeneration. In this case, administration regimens containing compounds of formula (I) and / or tautomers thereof may be administered to the substantia nigra, pallidum, and / or urinary tract. In another embodiment, the atrophy or degradation of the globus pallidus, subthalamic nucleus, and / or cerebellum is reduced. In this context, administration regimens comprising compounds of formula (I) and / or their tautomers are improves endocrine function, which can lead to improved behavior, improved survival (i.e., longevity) and brain degeneration In another embodiment, the compound of formula (I) and / or its Dosage regimens containing tautomers of tau inhibit aggregation of abnormal tau protein or fragments of tau protein. In another embodiment, the compound of formula (I) and / or its Dosage regimens containing tautomers ameliorate the loss of neuroprotective proteins in the brain. In one embodiment, the administration of a compound of formula (I) and / or a tautomer thereof The regimen reduces the decrease in brain-derived neurotrophic factor and Bcl2. In this context, administration regimens comprising compounds of formula (I) and / or tautomers thereof may be administered, e.g. Ba[ 18Cerebral glomerulonephritis, as assessed by [F]-fluoro-deoxyglucose PET Course Improves metabolic decline.

[0052] Furthermore, in a preferred embodiment, the compound of formula (I) and / or its tautomer The dosing regimen, which includes: Improve your car and score by one or more of the following: - PSP Rating Scale (PSPRS) (28-item scale) - Modified PSPRS (10-item subscale) - Corticobasal Ganglionic Function Scale (CBFS) - PSP Functional Impairment Scale (PSPFDS) - Schwab and England Activities of Daily Living (SEADL) - Clinical Global Impression of Change (CGI-C) - Progressive Supranuclear Palsy Quality of Life Scale (PSP-QoL) - Montreal Cognitive Assessment (MoCA) - Dimensional Apathy Scale (D AS) - Color Trails Exam Part 1 and 2 (CTT -1 and CTT-2) - Letter fluency test - Neurodegenerative and neuroinflammatory CSF biomarkers, e.g., neurodegeneration panel: total tau , p-tau, NfL and neuroinflammation panel - Total brain volume measured by MRI Brain volume - Regional (midbrain, frontal lobe, third ventricle) volumes measured by brain volumetric MRI - Plasma and CSF (NfL, total tau, p-tau) concentrations.

[0053] To meet the required target occupancy in the brain as determined above, the concentration of the compound of formula (I) in plasma and / or a specific concentration of its tautomer needs to be achieved in human patients. Brain enzymes, receptors, or target occupancy can be used as positron emission tomography (PET) tracers. The selective radiolabeled O-GlcNAcase inhibitor used in the present invention is a compound of formula (I). Quantification was performed by competitive displacement with 18 F]-Radiolabeled selective O-GlcNAcase As an inhibitor 18 F]-LSN3316612 was selected because it O-GlcNAcas in the brain as a PET tracer for genomic DNA studies and in preclinical studies e because it has been shown to exhibit suitable selectivity and pharmacokinetics for the determination of enzymes. (Paul S. et al. J.Nucl.Med.2019,60(1),129-134) Other suitable PET tracers will produce similar results. The required target occupancy and plasma concentration of the drug will be The correlation between the concentration and the PET tray concentration of the compound of formula (I) and / or its tautomers was The plasma concentration of the compound of formula (I) and / or its tautomers during competitive substitution of the serotonin is measured. It is established by

[0054] Thus, the plasma concentrations of the compounds of formula (I) and / or their tautomers are shown below. It has been found that favorable target occupancy in the brain can be achieved when the agonist is as described. Plasma concentrations were measured and are shown at steady state unless otherwise indicated.

[0055] Throughout this specification, all embodiments of the invention are referred to as , may be combined with any other embodiment of the invention disclosed herein. Such combination embodiments are more preferred when the individual embodiments they contain are more preferred. preferable.

[0056] In a preferred embodiment, the plasma concentration of the compound of formula (I) and / or its tautomers is The trough concentration is at least about 35 ng / mL, preferably at least about 45 ng / mL. mL or 55 ng / mL or 65 ng / mL or 80 ng / mL, more preferably and a trough of at least about 100 ng / mL or at least about 125 ng / mL. or 155 ng / mL or 195 ng / mL, most preferably at least All were approximately 270ng / mL, 335ng / mL, 610ng / mL, 755ng / mL, and 1 290ng / mL or 1600n / mL.

[0057] In a highly preferred embodiment, a compound of formula (I) and / or a tautomer thereof The plasma concentration of at least about 55 ng / mL or 80 ng / mL at the trough level, more preferably at at least about 125 ng / mL or 195 ng / mL at the trough level, most preferably at least about 335 ng / mL, 755 ng / mL, or 1600 ng / mL Possible.

[0058] In another preferred embodiment, the compound of formula (I) and / or its tautomers The range of plasma trough concentrations in the human body is about 45 ng / mL to about 2000 ng / mL, preferably or about 55 ng / mL to about 1600 ng / mL. The trough plasma concentration range is about 100 ng / mL to about 2000 ng / mL, preferably In another embodiment, the concentration is about 125 ng / mL to about 1600 ng / mL. The trough plasma concentration range is about 155 ng / mL to about 2000 ng / mL, preferably In another embodiment, the concentration is about 125 ng / mL to about 1600 ng / mL. The trough plasma concentration range is about 270 ng / mL to about 2000 ng / mL, preferably The range is approximately 335 ng / mL to approximately 1600 ng / mL.

[0059] Over a 24-hour period during treatment with a medicament or formulation containing a compound of formula (I) at steady state The average plasma concentration of the compound of formula (I) and / or its tautomers is preferably at least at least about 155 ng / mL, at least about 195 ng / mL, or preferably at least Approximately 270ng / mL, 335ng / mL, 380ng / mL, or 475ng / mL, More preferably, at least about 610 ng / mL or 750 ng / mL, and most preferably at least at least about 1290 ng / mL or 1600 ng / mL.

[0060] In a highly preferred embodiment, treatment with a medicament or formulation comprising a compound of formula (I) The mean plasma concentrations of the compound of formula (I) and / or its tautomers over a 24-hour period in at least about 195 ng / mL, preferably at least about 335 ng / mL or 475 ng / mL, more preferably at least about 750 ng / mL, and most preferably at least It is approximately 1600ng / mL.

[0061] In one embodiment, a compound of formula (I) and / or a tautomer thereof or within 24 hours during treatment with a medicament or formulation containing a pharmaceutically acceptable solvate or salt of The mean plasma concentration range of the compound of formula (I) and / or its tautomers is about 270 ng / mL to about 2000 ng / mL, preferably about 335 ng / mL to about 1600 ng / mL mL. In another embodiment, the compound of formula (I) and / or its tautomer Treatment with a medicament or formulation containing the isomer or a pharmaceutically acceptable solvate or salt thereof of the mean plasma concentrations of the compound of formula (I) and / or its tautomers over a 24-hour period The range is from about 380 ng / mL to about 5000 ng / mL, preferably from about 475 ng / mL to about In another embodiment, the compound of formula (I) and / or or a tautomer thereof or a pharmaceutically acceptable solvate or salt thereof of the compound of formula (I) and / or its tautomers over a 24-hour period during treatment with the formulation The mean plasma concentration ranges from about 490 ng / mL to about 10,000 ng / mL, preferably about 61 5ng / mL to approximately 8330ng / mL.

[0062] In one embodiment, the compound of formula (I) and / or its analogs at steady state The plasma concentration of the variant is at least about 155 ng / mL or 195 ng / mL at trough. mL, while the concentration of the compound of formula (I) and / or its tautomers over 24 hours The mean plasma concentration is at least about 270 ng / mL or 335 ng / mL.

[0063] In a highly preferred embodiment, the compound of formula (I) and / or The plasma concentration of the tautomer is at least about 195 ng / mL at the trough. Meanwhile, the mean plasma concentrations of the compound of formula (I) and / or its tautomers over a 24-hour period are At least about 335 ng / mL.

[0064] In another embodiment, the compound of formula (I) and / or its derivatives at steady state The plasma concentrations of the tautomers of g / mL, while the compound of formula (I) and / or its tautomers over 24 hours The average plasma concentration in the body is at least about 610 ng / mL or 755 ng / mL.

[0065] In a highly preferred embodiment, the compound of formula (I) and / or The plasma concentration of the tautomer is at least about 335 ng / mL at the trough. Meanwhile, the mean plasma concentrations of the compound of formula (I) and / or its tautomers over a 24-hour period are At least about 755 ng / mL.

[0066] The present invention relates to a compound of formula (I) and / or its tautomers or pharmaceutically acceptable solvents thereof. and administering a medicament or pharmaceutical composition containing the solvate or salt thereof to an individual in need thereof, for example, a patient suffering from a neurological disorder or or a neurodegenerative disease, such as mild to moderate AD or PSP. , the desired concentration of the compound of formula (I) and / or its tautomers in plasma over a period of time. The compound of formula (I) provides a dosing regimen to obtain a desired pharmacokinetic profile of the compound of formula (I). By maintaining a desired plasma concentration of the compound and / or its tautomer, High target occupancy is achieved.

[0067] The preferred pharmacokinetic profile and / or endpoints are preferably, e.g. Approx. 100mg, approx. 120mg, approx. 150mg, approx. 180mg, approx. 200mg, approx. 250m g, about 300mg, about 350mg, about 375mg, about 400mg, about 450mg, about 50 0 mg or about 750 mg of a compound of formula (I) and / or its tautomer (which is and one or more monoclonal antibodies containing the compound (which may also be administered in the form of a pharmaceutically acceptable solvate or salt thereof). This can be achieved by administration of a dosage form.

[0068] The preferred pharmacokinetic profile and / or endpoints are more particularly those of the formula ( Specific daily doses, preferably daily oral doses, of compounds I) and / or their tautomers This can be achieved by administering about 240 mg to about 1500 mg per day. , more preferably about 300 mg to about 1200 mg per day, and most preferably about 1200 mg per day This can be achieved by administering a dose ranging from about 360 mg to about 1000 mg. In preferred embodiments, the daily dose is about 300 mg or about 450 mg per day. or about 500 mg, or about 600 mg, or about 900 mg, or about 1000 mg.

[0069] In a preferred embodiment, the compound of formula (I) and / or its tautomer is administered daily. The doses are determined by dividing the respective fractions of the daily dose of the compound of formula (I) and / or its tautomers by 100 mg / kg. BID or TID administration regimens, including BID or TID administration This is preferably one containing a compound of formula (I) and / or a tautomer thereof. or by administering two unit dosage forms, e.g., tablets or capsules, per dose. It is achieved.

[0070] In a preferred embodiment where a BID or TID administration regimen is applied, An immediate release formulation of the compound of formula (I) and / or its tautomer is preferred. Another embodiment in which once-daily (QD) administration of CI 16248 and / or its tautomers is applied. In the above, modified, controlled or delayed or sustained release formulations are preferred, more preferably A steady state (i.e., with a large "burst" effect where most of the dose is released at once) It is a formulation that releases the dose in a non-invasive manner.

[0071] The immediate release formulations and immediate release unit dosage forms according to the present invention are in the form of tablets or capsules. Immediately after the coating-like shell of each dosage form has dissolved, the compound of formula (I) and / or or a tautomer thereof or a pharmaceutically acceptable solvate or salt thereof is released. This is preferably designed to be a compound of formula (I) and / or a tautomer thereof Rapid absorption and rapid systemic distribution of benzodiazepine in the body, i.e., rapid increase in its blood concentration. The immediate release formulations and immediate release unit dosage forms according to the present invention are packaged in sachets or pouches. This also includes pharmaceutical preparations.

[0072] Preferably, the immediate release dosage form according to the present invention exhibits a solubility in water of 1000 mg / L in a USP paddle test. 0.1% cetyltrimethylammonium bromide ( CTAB) at a paddle speed of 75 rpm, and at 45 minutes, the compound of formula (I) and / or or release at least 75%, preferably at least 95%, of its tautomers, and / or at least one of the compounds of formula (I) and / or its tautomers at 15 minutes. Most preferably, the immediate release dosage form according to the present invention is the same as that described in Example 4. In the USP paddle test according to the present invention, the compound of formula (I) and / or At least 75% of the tautomers were released.

[0073] In a highly preferred embodiment, a compound of formula (I) and / or a tautomer thereof or a pharmaceutically acceptable solvate or salt thereof. including the respective doses and administration frequencies as follows: and its tautomer at a dose of approximately 150 mg three times a day (TID) or at a dose of approximately 250 mg, 1 twice daily (BID), or preferably at a dose of about 300 mg, three times daily, or ) compound at a dose of 500 mg, twice daily.

[0074] Individual patients may tolerate the preferred doses and administration regimens disclosed herein. Even if not clinically effective for their respective indications at low doses and low dosing regimens, Beneficial effects may still be seen. This low dose and low administration regimen is more preferably This is more specifically disclosed in embodiments A to F.

[0075] A. Compounds and / or tautomers thereof for use in methods of treating human subjects wherein the method comprises reacting one or more units comprising a compound of formula (I) and / or a tautomer thereof The dosage form is assigned a certain dose and daily dosing frequency. wherein the dose of the compound of formula (I) and / or its tautomer is administered over time, including repeated administration at orally administered in the range of about 75 mg to about 250 mg of the compound and / or its tautomer. Gender body.

[0076] B. A dose of a compound of formula (I) and / or a tautomer thereof is orally administered and is about 125 mg to about 250 mg of a compound for use according to embodiment A and / or Its tautomer.

[0077] C. Repeated administration of the compound of formula (I) and / or its tautomers remains constant A compound and / or a tautomer thereof for use according to embodiment A or B.

[0078] D. The daily administration frequency of the compound of formula (I) and / or its tautomer is twice a day or The compound for use according to any one of embodiments A to C, and / or is its tautomer.

[0079] E. When a daily dose of a compound of formula (I) and / or a tautomer thereof is administered orally, In any one of the above embodiments A to D, the range is about 225 mg to 250 mg per day. 1. A compound and / or a tautomer thereof for use according to claim 1.

[0080] F. An oral dose of about 75 mg of the compound of formula (I) and / or its tautomer is administered 3 times daily. The method of any one of embodiments A to E, comprising administering an oral dose of about 125 mg twice daily. 10. A compound and / or a tautomer thereof for use according to any one of claims 1 to 9.

[0081] In one embodiment, the present invention provides a medicament comprising a compound of formula (I) and Compounds of formula (I) and / or their tautomers or pharmaceutically acceptable solvates or a salt thereof, wherein the compound of formula (I) ) and / or a tautomer thereof at about 1650 to about 7390 ng / mL I) and / or its tautomer in an amount sufficient to provide a plasma Cmax of the compound. In another embodiment, the compound of formula (I) and / or its tautomers The plasma Cmax of the body is preferably about 1940 to about 6750 ng / mL. In a more preferred embodiment, the C of the compound of formula (I) and / or its tautomer Maximum is approximately 2050ng / mL to approximately 2160ng / mL, or approximately 2200ng / mL About 2950 ng / mL, or about 3030 ng / mL to about 3150 ng / mL, or about 4250ng / mL to approximately 4350ng / mL, or approximately 4400ng / mL to approximately 6000 ng / mL, or about 6130 ng / mL to about 6250 ng / mL.

[0082] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound of formula (I) or a pharmaceutically acceptable solvate or salt thereof. ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) and / or its tautomer at about 1650 to about 3520 ng / mL of a compound of formula (I) in an amount sufficient to produce a plasma Cmax of the compound and / or its tautomer. In another embodiment, the compound of formula (I) and / or its tautomers The plasma Cmax is preferably about 1940 to about 3340 ng / mL. In a preferred embodiment, Cmax is about 2050 ng / mL to about 2160 ng / mL. or about 2200 ng / mL to about 2950 ng / mL, or about 3030 ng / mL to about It is 3150ng / mL.

[0083] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) and / or its tautomer at about 1650 to about 2930 ng / mL of a compound of formula (I) in an amount sufficient to produce a plasma Cmax of the compound and / or its tautomer. In another embodiment, the compound of formula (I) and / or its tautomers The plasma Cmax is preferably about 1940 to about 2380 ng / mL. In a preferred embodiment, the Cmax of the compound of formula (I) and / or its tautomers is about 2050 ng / mL or about 2100 ng / mL or about 2160 ng / mL or It is about 2200 ng / mL or about 2250 ng / mL.

[0084] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) and / or its tautomer at about 2500 to about 3520 ng / mL of a compound of formula (I) in an amount sufficient to produce a plasma Cmax of the compound and / or its tautomer. In another embodiment, the compound of formula (I) and / or its tautomers The plasma Cmax is preferably about 2700 to about 3340 ng / mL. In a preferred embodiment, the Cmax of the compound of formula (I) and / or its tautomers is about 2950 ng / mL or about 3000 ng / mL or about 3030 ng / mL or It is about 3100 ng / mL or about 3150 ng / mL.

[0085] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) and / or its tautomer at about 3580 to about 7390 ng / mL of in an amount sufficient to produce a plasma Cmax of the compound and / or its tautomer. In another embodiment, the compound of formula (I) and / or its tautomers The plasma Cmax is preferably about 3910 to about 6750 ng / mL. In a preferred embodiment, the Cmax of the compound of formula (I) and / or its tautomers Approximately 4250ng / mL to approximately 4350ng / mL, or approximately 4400ng / mL to approximately 60 00ng / mL, or about 6130ng / mL to about 6250ng / mL.

[0086] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) and / or its tautomer at about 3580 to about 5600 ng / mL of a compound of formula (I) in an amount sufficient to produce a plasma Cmax of the compound and / or its tautomer. In another embodiment, the compound of formula (I) and / or its tautomers The plasma Cmax is preferably about 3910 to about 4790 ng / mL. In a preferred embodiment, the Cmax of the compound of formula (I) and / or its tautomers is about 4250ng / mL or about 4300ng / mL or about 4350ng / mL or It is about 4400 ng / mL or about 4450 ng / mL.

[0087] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) and / or its tautomer at about 5150 to about 7390 ng / mL of a compound of formula (I) in an amount sufficient to produce a plasma Cmax of the compound and / or its tautomer. In another embodiment, the compound of formula (I) and / or its tautomers The plasma Cmax is preferably about 5510 to about 6750 ng / mL. In a preferred embodiment, the Cmax of the compound of formula (I) and / or its tautomers is about 6000ng / mL or about 6100ng / mL or about 6130ng / mL or It is about 6200 ng / mL or about 6250 ng / mL.

[0088] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) About 13,850 to about 90,500 mg of the compound and / or its tautomer * h / mL formula

[0033] Providing a 24-hour plasma AUC of compound (I) and / or its tautomers In another embodiment, the compound of formula (I) and / or The plasma AUC of the compound or its tautomer over 24 hours is preferably about 18550 to about 63 220ng * h / mL. In another more preferred embodiment, The AUC of the compound and / or its tautomer over 24 hours is approximately 20,000 mg * h / mL ~ approx. 23200ng * h / mL, or approximately 25750 ng * h / mL ~ approx. 2900 0ng * h / mL, or approximately 43,000 ng * h / mL ~ approx. 46780ng * h / mL, or approximately 52680ng * h / mL ~ approx. 55000ng * h / mL.

[0089] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) About 13850 to about 40365 mg of the compound and / or its tautomer * h / mL formula

[0033] Providing a 24-hour plasma AUC of compound (I) and / or its tautomers In another embodiment, the compound of formula (I) and / or The plasma AUC of the compound or its tautomer over 24 hours is preferably about 18550 to about 30 900ng * h / mL. In another more preferred embodiment, The AUC of the compound and / or its tautomer over 24 hours is approximately 20,000 mg * h / mL ~ approx. 23200ng * h / mL, or approximately 25750 ng * h / mL ~ approx. 2900 0ng * h / mL.

[0090] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) About 13850 to about 39800 mg of the compound and / or its tautomer * h / mL formula

[0033] Providing a 24-hour plasma AUC of compound (I) and / or its tautomers In another embodiment, the compound of formula (I) and / or The plasma AUC of the compound or its tautomer over 24 hours is preferably about 18550 to about 27 850ng * h / mL. In another more preferred embodiment, The AUC of the compound and / or its tautomer over 24 hours is approximately 20,000 mg * h / mL or approximately 21,000 ng * h / mL or approximately 23,200 ng * h / mL or approximately 2 5000ng * h / mL or approximately 26,000 ng * h / mL.

[0091] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) About 15,990 to about 40,365 mg of the compound and / or its tautomer * h / mL formula

[0033] Providing a 24-hour plasma AUC of compound (I) and / or its tautomers In another embodiment, the compound of formula (I) and / or The plasma AUC of the compound or its tautomer over 24 hours is preferably about 20600 to about 30 900ng * h / mL. In another more preferred embodiment, The AUC of the compound and / or its tautomer over 24 hours is approximately 22,000 mg * h / mL or approximately 23,000 ng * h / mL or approximately 25750ng * h / mL or approximately 2 5750ng * h / mL or approximately 28,000 ng * h / mL or approximately 29,000 ng * h / mL.

[0092] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) About 30150 to about 90500 mg of the compound and / or its tautomer * h / mL formula

[0033] Providing a 24-hour plasma AUC of compound (I) and / or its tautomers In another embodiment, the compound of formula (I) and / or The plasma AUC of the compound or its tautomer over 24 hours is preferably about 3742 to about 63 220ng * h / mL. In another more preferred embodiment, The AUC of the compound and / or its tautomer over 24 hours is approximately 43,000 mg * h / mL ~ approx. 46780ng * h / mL, or approximately 52680 ng * h / mL ~ approx. 5500 0ng * h / mL.

[0093] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) About 30150 to about 74230 mg of the compound and / or its tautomer * h / mL formula

[0033] Providing a 24-hour plasma AUC of compound (I) and / or its tautomers In another embodiment, the compound of formula (I) and / or The plasma AUC of the compound or its tautomer over 24 hours is preferably about 3742 to about 56 130ng * h / mL. In another more preferred embodiment, The AUC of the compound and / or its tautomer over 24 hours is approximately 43,000 mg * h / mL or approximately 44,000 ng * h / mL or approximately 46780ng * h / mL or approximately 4 9000ng * h / mL or approximately 50,000 ng * h / mL.

[0094] In one embodiment, the present invention provides a compound of formula (I) and / or a tautomer thereof and a pharmaceutical comprising the compound or a pharmaceutically acceptable solvate or salt thereof, and a compound of formula (I ) and / or a tautomer thereof or a pharmaceutically acceptable solvate thereof provides a method of administering to an individual a medicament or pharmaceutical composition comprising a salt, wherein the compound of formula (I) About 30,750 to about 90,500 mg of the compound and / or its tautomer * h / mL formula

[0033] Providing a 24-hour plasma AUC of compound (I) and / or its tautomers In another embodiment, the compound of formula (I) and / or The plasma AUC of the compound or its tautomer over 24 hours is preferably about 42140 to about 63 220ng * h / mL. In another more preferred embodiment, The AUC of the compound and / or its tautomer over 24 hours is approximately 49,000 ng* h / mL or approximately 50,000 ng * h / mL or approximately 52680ng * h / mL or approximately 5 4000ng * h / mL or approximately 55,000 ng * h / mL.

[0095] The time to reach plasma Cmax of the compound of formula (I) and / or its tautomers is The time period depends on the individual, but is preferably 0.5 to 6 hours. In this study, tmax (time to Cmax) was approximately 0.75 to 2 hours, or approximately 1.00 Preferably, tmax is 1 to about 1.75 hours, or about 1.5 hours after administration. It's in the 1.5 hour range.

[0096] Furthermore, the present invention is applicable to about 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months Months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, preferably To achieve these levels for more than one year, the compound of formula (I) and / or This involves repeated administration of the tautomer.

[0097] All dosages given throughout this specification are for compounds of formula (I) and / or refers to the amount of each tautomer in the form of its free base. Any dose or administration of the acid addition salts of the compounds of I) and / or their tautomers may be The formula (I) should be adjusted accordingly to take into account the additional molecular weight of each acid. The same applies analogously to solvates of compounds of formula (I) and / or their tautomers.

[0098] The compounds of formula (I) and / or their tautomers may be used in combination with one or more of the respective pharmaceutically usable compounds. Although the compounds may be administered in the form of a suitable solvate or salt, plasma concentrations are referred to throughout this specification as Liberation of the respective base forms, i.e., compounds of formula (I) and / or their tautomers It is understood that the compound is shown as such.

[0099] In a preferred embodiment, the compound of formula (I) and / or its tautomer is They are administered in the form of their respective hydrochloride salts.

[0100] Preferably, the administration intervals are regular or follow a regular pattern. More preferably, The medicament of the present invention is administered twice or three times a day. Most preferably, the administration interval is twice a day. In the case of administration, the dose is about 4 to about 10 hours or about 12 hours, and in the case of administration three times a day during the day about 4 to about 6 hours, followed by a non-administration period overnight, for example, 8 to 16 hours.

[0101] A low-dose regimen may comprise administering about 450 mg of the compound of formula (I) and / or its tautomer. or about 500 mg daily. A lower dose regimen may be used, for example, at about 900 mg. before or after a higher dose regimen, such as a daily dose of about 1000 mg or It can be used for.

[0102] The dose of the compound of formula (I) and / or its tautomer is preferably administered twice or three times a day. at least about 4 months, preferably at least about 6 months or at least about 8 months Oral administration for at least about 1 year, or more preferably for at least about 2 years, may improve cognitive function. amelioration or attenuation of decreased blood flow, progression of biochemical disease markers and / or plaque pathology bring about.

[0103] In one embodiment, the preferred dosage form is a unit dosage form, e.g., a tablet. In another embodiment, the preferred dosage form is a capsule. The form is a powder, preferably contained in a sachet. The medicament or composition may be used to assess progression of biochemical disease markers, plaque pathology, quality of life indicators or results in an improvement or alleviation of the reduction of any combination of disease parameters.

[0104] The cognitive decline may preferably be characterized by cognitive testing. The reduction in symptoms is at least 25% compared to placebo-treated individuals, and more preferably at least 25% compared to placebo-treated individuals. It is preferred that the ratio is at least 40%, and even more preferred that it is at least 60%. Individuals with presumably mild to moderate Alzheimer's disease who were treated with a placebo were After a period of time (e.g., 1 year), the ADAS-cog test showed a score approximately 5.5 points higher. While individuals treated with the compositions of the present invention over the same period would be expected to show a significant improvement in ADAS-c score only about 3.3 points higher on the OG scale (i.e., compared to untreated individuals) 60% cognitive decline) or 2 if treated over the same specified period. 0.2 points higher (i.e., a 40% cognitive decline compared to untreated individuals) (see below).

[0105] In particular embodiments of this aspect of the invention, compounds of formula (I) and / or Tautomers or pharmaceutically acceptable salts thereof, optionally with release agents release agent and any additional ingredients that may be used. The dosage is provided as a constituted medicament or pharmaceutical composition.

[0106] In another particular embodiment of this aspect of the invention, the unit dosage form, preferably a tablet, The dosage is provided as a medicament or pharmaceutical composition that is a capsule or a unit dosage form. Preferably, the compound of formula (I) and / or its tautomer, microcrystalline cellulose, colophony This aspect of the invention is comprised of silicon dioxide and magnesium stearate. In another particular embodiment, the compound of formula (I), microcrystalline cellulose, colloid Silicon dioxide and magnesium stearate (all lactose monohydrate, hydrolyzed Xylpropyl methylcellulose, titanium dioxide, triacetin / glycerol triacetate and a pharmaceutical composition which is a capsule comprising the compound (encapsulated in iron oxide and methacrylate). and administer the dose.

[0107] Pharmaceutical preparations may be administered in any desired suitable manner, for example, orally (including bucally or sublingually), rectally, Nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or Such formulations may be adapted for administration by various methods known in the pharmaceutical arts. for example, by mixing the active ingredient with an excipient or auxiliary agent. It can be done.

[0108] The pharmaceutical compositions of the present invention may contain conventional solid or liquid carriers, diluents and / or excipients. and with the usual adjuvants used in pharmaceutical manufacturing technology, in appropriate dosages. The amount of excipients that are combined with the active ingredient to produce a single dosage form is determined by known methods. The dosage will vary depending on the host being treated and the particular mode of administration. Suitable excipients include enteral (e.g., The compounds of formula (I) are suitable for various routes of administration, such as oral, parenteral or topical application. Examples of suitable excipients include organic or inorganic substances that do not react with the compound or its salt. Water, vegetable oil, benzyl alcohol, alkylene glycol, polyethylene glycol glycerol triacetate, gelatin, carbohydrates such as lactose or starch These include glycerin, magnesium stearate, talc and petrolatum.

[0109] In a highly preferred embodiment of the invention, the pharmaceutical composition is adapted for oral administration. The formulations can be sterilized and / or contain adjuvants, such as carrier proteins (e.g., serum Albumin), lubricant, preservative, stabilizer, filler, chelating agent, antioxidant, solvent, binder , suspending agents, wetting agents, emulsifying agents, salts (to influence osmotic pressure), buffer substances The composition may contain coloring agents, flavoring agents, and one or more other active substances, such as one or more vitamins. Additives are well known in the art and are used in a variety of formulations.

[0110] Pharmaceutical preparations adapted for oral administration may be presented as discrete units, such as capsules or tablets; powders; or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam edible or administered as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion Ugh.

[0111] Of course, in addition to the ingredients specifically mentioned above, the formulation may contain other ingredients that may be present in the formulation, such as those specific to the particular type of formulation. The present invention may also include other substances commonly used in the art for the treatment of oral administration. Suitable formulations may include flavoring agents.

[0112] Preferred examples of capsule or tablet core formulations according to the present invention are those containing, preferably, e.g., the hydrochloride salt and / or tautomers thereof, fillers, binders, It includes a disintegrant, a glidant, a dry binder, a lubricant and optionally a solvent.

[0113] A highly preferred example of a capsule or tablet core formulation is a hydroxybenzoate, preferably containing the hydrochloride salt, e.g. a compound of formula (I) and / or a tautomer thereof in the form of a suitable salt, microcrystalline cellulose, polyvinyl alcohol, dextrose, croscarmellose sodium, silica, copovidone and sodium stearyl fumarate and optionally a solvent, such as water.

[0114] Furthermore, the pharmaceutical compositions and medicaments according to the present invention may be administered alone or in combination with other treatments. The use of multiple active pharmaceutical ingredients in a pharmaceutical composition or medicament can result in synergistic effects. The effect can be achieved, i.e., in this case, the compound of formula (I) and / or its tautomers The active ingredient is combined with at least one other substance as an active ingredient. can be used sequentially and contain a compound of formula (I) and another pharmaceutically active ingredient or substance The compound may be formulated into a single unit dosage form containing both the For example, WO 2008 / 025170), and the pharmaceutical composition according to the invention. They are useful in medicine and pharmacy.

[0115] In some embodiments, pharmaceutical compositions and medicaments according to the invention and The administration regimen may be used to treat, for example, a neurodegenerative disease, an inflammatory disease, a cardiovascular disease, an immunomodulatory disease, or To treat any of the conditions described herein, the combination therapy may include O-GlcNAca any other active substance or pharmaceutical composition that may be useful in modulating se activity In some embodiments, the pharmaceutical composition of the present invention may be provided in combination with other pharmaceutical compositions. The pharmaceutical compositions and medicaments and administration regimens according to the present invention are useful for treating tauopathies, synucleinopathies, and one or more substances useful in the prevention or treatment of Alzheimer's disease and Alzheimer's disease. Examples of such substances may include, but are not limited to:

[0116] - acetylcholinesterase inhibitors (AChEIs), such as Aricept (A Ricept® (donepezil), Exelon® (rivastigmine), Razadyne® [Razadyne ER ( Registered trademark), Reminyl®, Nivalin® Registered Trademark), Galantamine, Cognex )® (tacrine), NMDA antagonists such as memantine [Acxura] (Axura®, Ebixa®)], Huperzine Huperzine A, Phenserine, Debi o)-9902 SR (ZT-1 SR), Zanapezil (TAK 0147), ganstigmine, NP7557, α7 nicotine Acetylcholine receptor agonist, 5-HT6 receptor antagonist, M1 muscarinic acetylcholine receptor agonists and positive allosteric modulators, and other substances that restore / enhance cholinergic signaling or exhibit cognitive-enhancing effects.

[0117] - Tau aggregation inhibitors, such as methylene blue, morphomers, etc.

[0118] - Intracellular and extracellular tau seeding by sequestration of tau through direct binding to tau and substances that block transcellular spread, such as tau antibodies and other protein / peptide derived Tau-binding substances.

[0119] - Vaccines that induce titers of tau-binding / sequestering antibodies.

[0120] - Microtubule stabilizing agents, such as AL-108, AL-208, paclitaxel, etc.

[0121] - Neuroprotective substances or those claimed to be such (e.g., AZP2 006).

[0122] - Anti-inflammatory substances, e.g. non-steroidal anti-inflammatory drugs, TNFα / anti-rheumatic drugs, e.g. Neubrel, Humira, etc.

[0123] - Reduce or modify tau expression and / or downregulate Aβ production activating siRNA, shRNA, gene therapy or CRISPER-derived therapeutics quality.

[0124] - Amyloid beta (Aβ) peptide lowering substances, such as β-secretase (BACE-1 ) or gamma-secretase inhibitors or modulators.

[0125] - Aβ monomer or oligomer binding biologics that remove senile plaques, such as Aβ antibodies , and Aβ vaccines that induce titers of such antibodies.

[0126] - Compounds that inhibit tau phosphorylation by inhibiting kinases, e.g., GSK3 Inhibitor [Tideglusib].

[0127] - TREM2 and CD33 binding / modulating drugs / antibodies / vaccines.

[0128] - Cholesterol-lowering drugs, such as Zocor / Lipitor or), ApoE4-targeted drugs.

[0129] - Antihypertensive drugs, such as diuretics, angiotensin-1 receptor blockers, angiotensin converting enzyme inhibitors, calcium channel blockers or beta-blockers.

[0130] - Mood stabilizers, such as antidepressants (e.g., fluoxetine, duloxetine, buprenorphine) pion, amitriptyline, imipramine).

[0131] - Medications for insomnia, such as zolpidem.

[0132] - Nutritional supplements, such as Coenzyme Q10.

[0133] - Dopamine agonists, e.g. carbiodopa / levodopa, monoaminooxidase inhibitors (razagiline), COMPT inhibitors, gene therapy, etc.

[0134] Lewy body / alpha-synuclein binding biologics, e.g., alpha-synuclein antibodies, and alpha-synuclein vaccines that induce titers of such antibodies.

[0135] - TDP43 or FUS binding biologics, e.g., TDP43 or FUS antibodies, and and TDP43 or FUS vaccines that induce titers of such antibodies.

[0136] - Progranulin modulators.

[0137] - Synaptic plasticity and / or neuronal networks to improve cognition Cell-based therapy to enhance

[0138] - Deep brain stimulation (DBS) stimulates neuronal pathways involved in memory and cognition To achieve this, the brain is primarily focused on key areas such as the fornix and / or basal nucleus of Meynert (and is limited to these areas). This involves implanting electrodes into the brain (not the brain itself) (Mirzadeh Z. et al. (2016) )J.Neural Transm(Vienna)123:775-783;Ponc e FA et al. (2016) J Neurosurg 125:75-84;Sankar T et al. (2015) Brain Stimulat 8:645-654; Lozano AM et al. (2016) J Alzheimers Dis 54:777-787; Kuh n J et al. (2015) Brain Stimulat 8:838-839).

[0139] In addition to the chronically applied drug therapies listed above, cell-based therapies, gene therapies, , short-term or more invasive brain treatments, including deep brain stimulation and targeted lesions of brain circuits. Long-term O-GlcNAcase inhibition may also be beneficial. Transplantation of iPSC cells in disease may generate cellular stress in cultured cells This was alleviated by treatment with an O-GlcNAcase inhibitor, This may improve function and survival during and after treatment. As outlined above, O-GlcNAc plays a key role in transcription, stress granule formation, and heat shock. Protein synthesis, altered metabolic flux, reduced endoplasmic reticulum (ER) stress and mitochondrial damage improved endocrine function (all of which contribute to the immediate and long-term function and survival of transplanted cells) These pathways may play a role in determining cell survival. It has also been associated with reduced cellular stress at the surgical site and Reduction of the neuroinflammatory response and subsequent neuroinflammatory response may also be beneficial.

[0140] In some embodiments, pharmaceutical compositions and medicaments according to the invention and The dosing regimen is intended to prevent or treat tauopathies, synucleinopathies, and Alzheimer's disease. The present invention may be administered in combination with one or more therapeutically useful substances. Examples of such substances include, but are not limited to: Although not clinically relevant, it ranges from generating neurons that can be transplanted into affected brain regions to improve cognition. Neurons can be generated directly from somatic cells (Vier Buchen T. et al. (2010) Nature 463:1035-1041; Zha ng SZ. et al. (2016) Stem Cells Int.2016:2452985 ;Addis RC. et al. (2011) PLoS ONE 6:e28719;Zhao J. et al. (2012) PLoS ONE 7:e41506; Lim MS. et al. (2015 ) J. Biol. Chem. 290:17401-17414) and / or neurospecific can be generated from induced pluripotent stem cells (iPSCs) using any combination of target transcription factors (Kim J. et al. (2011) Proc Natl Acad Sci USA 108 :7838-7843; Matsui T. et al. (2012) Stem Cells 30 :1109-1119;Sheng C. et al. (2012) Cell Res 22:20 8-218;Lujan E. et al. (2012) Proc Natl Acad Sci USA 109:2527-2532; Lim MS et al. (2015) J Biol Ch em 290:17401-17414;Han DW et al. (2012) Cell Ste. m Cell 10:465-472).

[0141] The present invention also provides compounds of formula (I) and / or pharmaceutically acceptable salts and solutions thereof. From separate packs containing an effective amount of the vehicle and an effective amount of another drug containing a pharmaceutically active ingredient. The set may be packaged in a suitable container, e.g. a box, individual bottles, a bag or The set may comprise, for example, a compound of formula (I) and / or a pharmaceutical composition thereof. and a further unit dosage form each containing an effective amount of a salt and solvate thereof that is acceptable for The active pharmaceutical ingredient in unit dosage form, such as a tablet or in dissolved or lyophilized form. and an effective amount of another medicament comprising:

[0142] The pharmaceutical composition and medicament according to the present invention can be administered once or several times before or after the onset of a disease. The pharmaceutical compositions and medicaments described above may be administered to act as therapeutic agents. A therapeutically relevant effect is one that alleviates to some extent one or more symptoms of a disorder or One or more physiological or biochemical parameters associated with or contributing to a disease or pathological condition partially or completely restores normal function, e.g., enhances the response and completely eliminates disease symptoms. Therefore, as long as the pharmaceutical composition and the medicament are administered at well-defined intervals, monitoring is a kind of In the sense of the present invention, the subject is considered to be in a state of physiological or pathological condition. If you have any prerequisites for the condition, such as a familial predisposition, genetic defect, or pre-existing disease, , preventive treatment is recommended.

[0143] Particularly preferred embodiments of the present invention are as follows.

[0144] A. Compounds of Formula (I) and / or Their Analogs for Use in Methods of Treatment of Human Subjects wherein the method comprises the step of preparing a compound of formula (I) and / or a tautomer thereof The above unit dosage forms are administered in a steady state containing the compound of formula (I) and / or its tautomers. A dose sufficient to maintain a plasma concentration of at least about 35 ng / mL at the trough and The compound of formula (I) and / or its analogs may be administered in a single dose, including multiple doses at a daily dosing frequency. Mutant.

[0145] B. A compound of formula (I) and / or a tautomer thereof, wherein the plasma concentration of the compound of formula (I) and / or a tautomer thereof is about 4 For the use described in embodiment A, the range of 5 ng / mL to about 2000 ng / mL is maintained. and / or tautomers thereof.

[0146] C. Compounds of Formula (I) and / or Their Analogs for Use in Methods of Treatment of Human Subjects wherein the method comprises the step of preparing a compound of formula (I) and / or a tautomer thereof The above unit dosage forms are administered over a 24-hour period at steady state with a compound of formula (I) and / or Use sufficient to maintain an average plasma concentration of the tautomer at least about 155 ng / mL. and / or is its tautomer.

[0147] D. Mean plasma concentrations of the compound of formula (I) and / or its tautomers over a 24-hour period and maintaining the blood glucose concentration in the range of about 270 ng / mL to about 2000 ng / mL. Compounds and / or tautomers thereof for use.

[0148] E. Compounds of Formula (I) and / or Their Analogs for Use in Methods of Treatment of Human Subjects wherein the method comprises the step of preparing a compound of formula (I) and / or a tautomer thereof The above unit dosage forms are each administered with about 1650 to about 7390 ng / mL of the compound of formula (I) and / or The dose and daily dose are sufficient to maintain the plasma Cmax of the tautomer at steady state. the compound of formula (I) and / or its tautomers, including repeated administration at a dosage frequency of Gender body.

[0149] F. Compounds of Formula (I) and / or Their Analogs for Use in Methods of Treatment of Human Subjects wherein the method comprises the step of preparing a compound of formula (I) and / or a tautomer thereof The above unit dosage forms are approximately 13850 to approximately 90500 ng * h / mL of the compound of formula (I) and and / or its tautomers at steady state over 24 hours. The compound of formula (I) and the compound of formula (I) are administered in a repeated dose and at a daily administration frequency sufficient to and / or its tautomers.

[0150] G. A dose of a compound of formula (I) and / or a tautomer thereof is orally administered and is about 150 The compound for use according to any one of the preceding embodiments, in the range of 100 mg to about 500 mg. and / or its tautomers.

[0151] H. A compound of formula (I) and / or a tautomer thereof having a plasma Cmax of about 3580 to about 7390 ng / mL of the compound for use according to embodiment E and / or its analogs. Mutant.

[0152] I. The plasma AUC over 24 hours of a compound of formula (I) and / or its tautomers Approximately 30,150 to 90,500 ng * h / mL and / or its tautomers.

[0153] J. A dose of a compound of formula (I) and / or a tautomer thereof is orally administered and is about 300 The compound for use according to any one of the preceding embodiments, in the range of 100 mg to about 500 mg. and / or its tautomers.

[0154] K. Repeated administration of the compound of formula (I) and / or its tautomers remains constant The compound for use according to any one of the preceding embodiments and / or a tautomer thereof body.

[0155] L. The daily administration frequency of the compound of formula (I) and / or its tautomer is twice a day or the compound for use according to any one of the preceding embodiments, three times a day; and / or Its tautomer.

[0156] M. When a daily dose of a compound of formula (I) and / or its tautomer is administered orally, In this case, the daily dose is about 240 mg to about 1500 mg. The compound and / or its tautomer for use in

[0157] N. about 150 mg three times a day, or about 250 mg twice a day, or about 300 mg, three times a day, or about 500 mg twice a day of a compound of formula (I) and / or its tautomers The compound and method for use according to any one of the preceding embodiments, comprising administering an oral dose of the compound. and / or its tautomers.

[0158] O. Human subjects suffer from or develop a disease or condition a compound for use according to any one of the preceding embodiments, which has an increased risk of / or its tautomer.

[0159] P. The use of embodiment O, wherein the disease or condition is selected from one or more proteinopathies. The compound and / or its tautomer for use.

[0160] Q. Your disease or condition is a neurological or neurodegenerative disease, diabetes, cancer, cardiovascular disease, and brain The compound and / or its for use according to embodiment O or P is selected from the group consisting of: Tautomer.

[0161] R. A disease selected from the group consisting of neurological or neurodegenerative diseases, diabetes, cancer, cardiovascular disease, and stroke. suffer from or have an increased risk of developing a disease or condition Compounds of formula (I) and / or tautomers thereof for use in methods of treating human subjects and wherein the method comprises administering about 150 mg three times a day, or about 250 mg twice a day, or about 300 mg three times a day, or about 500 mg twice a day of a compound of formula (I) and / or or a tautomer thereof, Its tautomer.

[0162] S. The disease or condition is one or more of a tauopathy, a synucleinopathy, and an Alzheimer's disease. AD, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment ( ALSci), argyrophilic granulopathy, behavioral disorder frontotemporal dementia (behavioral va riant frontotemporal dementia) (bvFTD), non-current Fluent and semantic variant primary progressive aphasia ntic variant primary progressive aphasia ) (nfv and svPPA), Bluit disease, cortical Basal ganglionic degeneration (CBD), dementia pugilistica, dementia with Lewy bodies (DLB), with calcification Diffuse neurofibrillary tangles les with calcification), Down's syndrome, familial British dementia , familial Danish dementia, frontal locomotion with parkinsonism linked to chromosome 17 frontotemporal dementia with park insonism linked to chromosome 17)(FTDP-1 7), Frontotemporal Lobar Degeneration (FTLD), Glioma, Ganglioneuroma, Gerstmann-Schöt Reussler-Scheinker disease, globular glial tauopathy tauopathy), Guadeloupe Parkinsonism, Hallervorden-Spatz Disease (neurodegenerative type 1 with brain iron accumulation), lead encephalopathy, lipofuscinosis, meningioangiomatosis, multisystemic encephalopathy Niemann-Pick disease, including myotonic dystrophy (MSA), myotonic dystrophy, and type C Niemann-Pick disease -Pick's disease, Pallidopontonigral degeneration eneration), Parkinson's disease, Parkinson's disease dementia (PDD), Guam Parkinsonism-dementia syndrome, Pick's disease (PiD), postencephalitic parkinsonism (PEP) , prion diseases [Creutzfeldt-Jakob disease (GJD) and variant Creutzfeldt- Creutzfeldt-Jakob disease (vCJD)], fatal familial insomnia, kuru, progressive epicortical gliosis progressive supercortical gliosis Supranuclear palsy (PSP), pure autonomic failure, Richardson's syndrome, subacute sclerosing global cerebral Tangle-only dementia, tuberous sclerosis, Huntington's disease or mild cognitive impairment (MCI), chronic traumatic encephalopathy, primary progressive aphasia, progressive non-fluency Aphasia, Semantic Dementia, Steele-Richardson-Olszewski Syndrome, Seizure Cancer, chronic and acute inflammation, Crohn's disease, neuroinflammation, subarachnoid hemorrhage (SAH), multiple sclerosis ataxia, Friedreich's ataxia, and adrenoleukodystrophy. and / or a tautomer thereof for use according to embodiment O, P, Q or R. Gender body.

[0163] T. The compounds and / or their tautomers may be pharmaceutically acceptable solvates and / or or a salt form of the compound and salts for use according to any one of the preceding embodiments. and / or its tautomers.

[0164] U. About 100mg, about 120mg, about 150mg, about 180mg, about 200mg, about 2 50mg, approximately 300mg, approximately 375mg, approximately 400mg, approximately 450mg, approximately 500mg or about 750 mg of a compound of formula (I) and / or a tautomer thereof. and optionally one or more pharmaceutically acceptable excipients.

[0165] V. about 150 mg, about 250 mg, about 300 mg, or about 500 mg of a compound of formula (I) The unit dosage form according to embodiment U, comprising the compound and / or a tautomer thereof.

[0166] W. A single unit dosage form according to embodiment U or V, wherein the unit dosage form is adapted to be administered orally. dosage form.

[0167] X. Embodiments U, V, or W, wherein the unit dosage form is in the form of a tablet, capsule, or sachet The unit dosage form according to any one of the preceding claims.

[0168] Y. The compound and / or its tautomers are pharmaceutically acceptable solvates and / or or a salt form.

[0169] Z. Any of embodiments A through T comprising administration of a unit dosage form according to any one of embodiments U through Y. 10. A compound and / or a tautomer thereof for use according to any one of claims 1 to 9.

[0170] Za. Suffering from or at increased risk of developing a disease or condition Compounds of formula (I) and / or tautomers thereof for use in a method of treating a human subject and wherein the method comprises administering about 150 mg three times a day, or about 250 mg twice a day, or or about 300 mg three times a day, or about 500 mg twice a day of a compound of formula (I) and and / or a tautomer thereof, comprising administering an oral dose of the compound of formula (I) and / or is its tautomer.

[0171] Further preferred embodiments of the present invention are as follows.

[0172] 1. Compounds of formula (I) and / or their tautomers or pharmaceutically acceptable solvents thereof One or more unit dosage forms containing a compound of formula (I) and a solvate or salt thereof at steady state or its tautomer at a plasma concentration of at least about 35 ng / mL at trough. a dosing regimen comprising repeated administration to a human subject at a dose and daily dosing frequency sufficient to hmm.

[0173] 2. The plasma concentration of the compound of formula (I) and / or its tautomer is about 4 The dosing regimen described in embodiment 1 maintains the blood glucose level in the range of 5 ng / mL to about 2000 ng / mL. hmm.

[0174] 3. Compounds of formula (I) and / or their tautomers or pharmaceutically acceptable solvents thereof One or more unit dosage forms containing a solvate or salt of formula (I) were administered over a 24-hour period at steady state. ) and / or its tautomers to a mean plasma concentration of at least about 155 ng / m administration to a human subject at a dose and daily frequency sufficient to maintain the Administration regimen.

[0175] 4. The mean plasma concentration of the compound of formula (I) and / or its tautomers is The method according to embodiment 3, wherein the concentration of α-glucan in the blood is maintained in the range of about 270 ng / mL to about 2000 ng / mL. Dosage regimen.

[0176] 5. Compounds of formula (I) and / or their tautomers or pharmaceutically acceptable solvents thereof One or more unit dosage forms containing a solvate or salt of about 1650 to about 7390 ng / mL of formula ( Maintaining the plasma Cmax of compound I) and / or its tautomer at steady state a dosing regimen comprising repeatedly administering the compound to a human subject at a dose and daily dosing frequency sufficient to achieve the desired effect.

[0177] 6. Compounds of formula (I) and / or their tautomers or pharmaceutically acceptable solvents thereof One or more unit dosage forms containing a solvent or salt, about 13850 to about 90500 mg * h / m The plasma AUC of the compound of formula (I) and / or its tautomers at L was determined over 24 hours. Repeated administration to human subjects at a dose and daily frequency sufficient to maintain normal body conditions and a dosing regimen comprising:

[0178] 7. The dose administered at the above daily administration frequency is orally administered, and is about 150 mg to about 500 mg. The dosing regimen of any one of the preceding embodiments, wherein the dose is in the range of 0.1 mg / kg or 0.25 mg / kg.

[0179] 8. The compound of formula (I) and / or its tautomer has a plasma Cmax of about 3580 to about 7390 ng / mL.

[0180] 9. The plasma AUC over 24 hours of the compound of formula (I) and / or its tautomer is Approximately 30,150 to 90,500 ng * h / mL.

[0181] 10. The dose administered at the above daily administration frequency is orally administered, and is about 300 mg to about 500 mg. The dosing regimen of any one of the preceding embodiments, wherein the dose is in the range of mg.

[0182] 11. The dosing regimen of any one of the preceding embodiments, wherein the repeated dose remains constant. Men.

[0183] 12. Any one of the preceding embodiments, wherein the daily administration frequency is twice daily or three times daily. The dosing regimen described above.

[0184] 13. A daily dose of a compound of formula (I) and / or its tautomer is administered orally In the case of any one of the above embodiments, the daily dose is about 240 mg to about 1500 mg. The dosing regimen described above.

[0185] 14. Approximately 150 mg three times a day, or approximately 250 mg twice a day, or approximately 300 mg , three times a day, or about 500 mg, twice a day, of a compound of formula (I) and / or its tautomer The dosing regimen of any one of the previous embodiments, comprising administration of an oral dose of the isomer.

[0186] 15. A method for treating neurological or neurological disorders, comprising administering the administration regimen described in any one of embodiments 1 to 14. A method for treating a condition selected from degenerative diseases, diabetes, cancer, cardiovascular disease and stroke.

[0187] 16. Approximately 150 mg three times a day, or approximately 250 mg twice a day, or approximately 300 mg , three times a day, or about 500 mg, twice a day, of a compound of formula (I) and / or its tautomer and administering to a human subject an oral dose of the isomer of the compound of formula (I) or (II) to treat a neurological or neurodegenerative disorder, a diabetes mellitus, or a combination thereof. A method for treating a condition selected from diabetic disease, cancer, cardiovascular disease and stroke.

[0188] 17. The condition is one or more of tauopathy, synucleinopathy, and Alzheimer's disease ( AD), amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSc) i), argyrophilic granulosis, behavioral variant frontotemporal dementia t frontotemporal dementia) (bvFTD), disfluency and Non-fluent and semantic variant primary progressive aphasia variant primary progressive aphasia)(nf v and svPPA), Bluit disease, corticobasal ganglia degeneration CBD, dementia pugilistica, dementia with Lewy bodies (DLB), diffuse dementia with calcification Diffuse neurofibrillary tangles with calcification), Down syndrome, familial British dementia, familial Danish dementia, a frontotemporal dementia with parkinsonism linked to chromosome 17 frontotemporal dementia with parkinso nism linked to chromosome 17)(FTDP-17), previous Temporal Lobar Degeneration (FTLD), glioma, ganglioneuroma, Gerstmann-Sträussler - Scheinker's disease, globular glial tauopathy pathology), Guadeloupe Parkinsonism, Hallervorden-Spatz disease (brain iron Neurodegeneration with accumulation (type 1), lead encephalopathy, lipofuscinosis, meningioangiomatosis, multiple system atrophy (MSA), myotonic dystrophy, Niemann-Pick disease (type C), pallidopontineural degeneration Pallido-ponto-nigral degeneration Parkinson's disease, Parkinson's disease dementia (PDD), Parkinsonism-dementia syndrome in Guam, Pick's disease (PiD), postencephalitic parkinsonism (PEP), prion disease [Creutzfeldt disease] Creutzfeldt-Jakob disease (GJD), variant Creutzfeldt-Jakob disease (vCJD) Fatal familial insomnia, kuru, progressive epicortical gliosis percortical gliosis, progressive supranuclear palsy (PSP), pure autonomic nervous system encephalopathy, Richardson's syndrome, subacute sclerosing panencephalitis, Tangle-only syndrome e-only) dementia, tuberous sclerosis, Huntington's disease or mild cognitive impairment (MCI), Chronic traumatic encephalopathy, primary progressive aphasia, progressive non-fluent aphasia, semantic dementia, STD Richardson-Olszewski syndrome, epilepsy, chronic and acute inflammation, claws Malignant encephalopathy, neuroinflammation, subarachnoid hemorrhage (SAH), multiple sclerosis (MS), Friedreich's movement As described in embodiment 15 or 16, which is selected from the group consisting of ataxia and adrenoleukodystrophy. A method of treating the condition.

[0189] 18. About 100mg, about 120mg, about 150mg, about 180mg, about 200mg, about 250mg, about 300mg, about 375mg, about 400mg, about 450mg, about 500mg or about 750 mg of a compound of formula (I) and / or a tautomer thereof or a pharmaceutically acceptable solvate, salt or tautomer thereof, and optionally one or more and a pharmaceutically acceptable excipient.

[0190] 19. A compound of formula (I) in an amount of about 150 mg, about 250 mg, about 300 mg, or about 500 mg and / or a tautomer thereof.

[0191] 20. The composition of embodiment 18 or embodiment 19, which is adapted for oral administration. Unit dosage form.

[0192] 21. Any of embodiments 18, 19 or 20, which is a tablet or capsule or sachet. A unit dosage form as described in any one of the items.

[0193] 22. A method for the administration of a compound according to any one of embodiments 1 to 14. 22. The unit dosage form of any one of embodiments 18, 19, 20 or 21.

[0194] All references cited herein are incorporated by reference into the present disclosure. It shall be so decided.

[0195] Example The compound of formula (I) is prepared according to WO / 2016 / 030443.

[0196] Example 1: Human O-GlcNAcase Enzyme Inhibition Assay in McIlvaine buffer (pH 6.5) in 2% DMSO Add 5 μl of the appropriate concentration of inhibitor (for dose-response curve calculation) to a 384-well plate. Then 20 nM of His-tag hOGA and 10 μM FL-GlcNAc [fluorescein mono-beta-D- (2-Deoxy-2-N-acetyl)glucopyranoside;Marker Gene Te Technologies Inc, M1485] into a 384-well plate to a final volume of 20 After incubation at room temperature for 60 minutes, add 10 μL of stop buffer (20 The reaction was stopped by the addition of 0 mM glycine, pH 10.75. exc 485 nm; (λ emm The wavelength (520 nm) was read on a PHERAstar instrument. The amount of measured fluorescence was plotted against the concentration of inhibitor to determine the IC 50 To calculate Sigmoidal dose-response curves were constructed. All values ​​were calculated by subtracting the background. Individual data were corrected (Thiamet G 3 μM = 100% inhibition), while 0.5% DMSO was considered as the control value (no inhibition).

[0197] Example 2: Pharmacodynamic Model : Total Protein O-GlcNAcylation Immunoassay (RL2 mAb, mesoscale electrophoresis) Electrochemical luminescence (ECL) assay The test compound was orally administered to C57BL / 6J mice. Typically, the range is 2 to 48 hours, preferably 4 to 24 hours, after which blood is collected and forebrain dissection is performed. Mice were sacrificed by decapitation. The right hemisphere was then placed in a 2 ml Precellys tube. The left hemisphere was placed in a tube, flash frozen in dry ice, and stored at -80°C. Place in a Dippendorff tube, flash freeze in dry ice, and store at -8°C until further processing. Blood samples were stored at 0°C. The collected samples were collected in tubes and kept at 4°C. After centrifugation at 3800 x g for 10 minutes at 4°C, each Transfer 50 μL of plasma from the sample to a 1.5 ml Eppendorf tube and store at -80°C. For the preparation of soluble brain proteins for immunoassay, protease inhibitors were used. Ice-cold Cytobuster Reagent (7100) containing bitters cocktail The hemispheres were homogenized in Merck Millipore buffer. After centrifugation at 7000 × g and 4 °C for 15 min, the supernatant was transferred to a polycarbonate tube (1 ml The supernatant was clarified by centrifugation at 100,000 x g for 1 hour at 4°C, and transferred to B Purchase the CA kit (23227 - Pierce, Rockford, IL) according to the manufacturer's instructions. Protein concentration was determined using the instructions.

[0198] Total Protein O-GlcNAcylation Immunoassay: Samples were randomized and 120 μg / ml (25 μl / well) of soluble brain protein was added. Multi-array 96-well high-bind plate (L15XB-3 High-bind-Mes The plates were directly coated onto Scale Discovery plates at 4°C overnight. 3 times with BS-T buffer), the plate was incubated with MSD Blocker A solution at room temperature ( After washing (three times with PBS-T buffer), O-GlcNA Mouse monoclonal antibody against the c region (RL2; MA1-072 - Thermo Scientific) Plates were incubated with 0.1 μg / ml of 1% ethanol at room temperature under agitation for 1 hour. For the ECL assay, after washing (three times with PBS-T buffer), μg / ml of SULFO-TAG™-conjugated anti-mouse secondary antibody (Meso Scale Discovery) and incubate the plate with agitation at room temperature for 1 hour, then block. After washing (three times with PBS-T buffer), 150 μl / well of 1×Read After adding Buffer T to the plate, the plate was imaged using a Sector Imager 6000 (Me The reading was conducted using the So Scale Discovery.

[0199] Example 3: Preclinical Model A. In vivo therapeutic effects on DSS colitis model: Zhao M, et al. (2018) EMBO Mol. Med. 10:e8736. Disodium dextran sulfate (DSS) is a negatively charged sulfated polysaccharide of approximately 36-50 kDa, and is used in beverages. Induces colitis when administered at 5% (weight / volume) in water for several days (Okayasu I (1990) Gastroenterology 98:694-702). Adult ( balb / c) mice were randomized and allowed to acclimate for one week. After this time, the mice were treated with a compound of formula (I) or The mice were administered vehicle by oral gavage for 21 days, which was 2 weeks before DSS treatment ( The study will begin on day 0 (day -14) and continue throughout DSS treatment and until the end of the experiment (day +9). On day 1, animals were given access to a 5% (wt / vol) DSS solution in their drinking water until day 5. The DSS solution is then removed and replaced with drinking water for an additional 4 days until day 9. From day 0 to the end of the experiment (+day 12), weight loss, loose stools and / or diarrhea, and stool Animals should be monitored daily for clinical signs of colitis, including the presence of occult or gross blood in the colon. + On day 12, or when the animals reach a humane endpoint, dissect the colon and The length of the colon is measured and its contents are observed. Samples of the distal colon are processed for histopathology. Another sample was homogenized for tissue cytokine analysis and stored at -80°C. The therapeutic effects of the test compounds were evaluated using the method described by Alenghat et al. 2013 (Alenghat T. (2013) Nature 504:153-157), including the following diseases: The evaluation is carried out by determining the scores for: i) weight loss, ii) stool appearance, iii) blood in the stool. presence, and iv) general appearance of the animal: - Weight loss (no weight loss = 0; <5% = 1; 5-10% = 2; 10-20% = 3; >2) 0%=4); - Stool (normal = 0; watery loose stool = 1; very loose, semi-formed = 2; liquid, sticky, or or inability to defecate = 3).

[0200] - Blood in stool (no blood = 0; visible blood in rectum = 1; visible blood on fur) blood = 2).

[0201] - General appearance (normal = 0; piloerection = 1; lethargy and piloerection = 2; reduced movement = 4).

[0202] Histological damage and inflammation were measured using the method described by Gilbert et al. (2012) (Gilbert S. et al. (2012) EMBO Mol.Med.4:109-124) Scoring parameters are edema (scale: 1-4), erosion / ulceration of the epithelial monolayer, formation (scale: 1-4), crypt loss / damage (scale: 1-4) and immune cell migration into the mucosa Including infiltration (scale: 1 to 4).

[0203] After treatment with a compound of formula (I), reduced weight loss, absence or reduction of blood in the stool, A decrease in disease scores due to better stool consistency and better general appearance is observed. Histological examination shows that treatment with compounds of formula (I) results in a significant reduction in tissue inflammation.

[0204] B. In vivo therapeutic effects on Parkinson's disease (PD) model (strain 61): Levine PM. et al. (2019) Proc. Natl. Acad. Sci. US A.116(5):1511-1519.

[0205] Wild-type human alpha-synuclein under the regulatory control of the mouse Thy-1 promoter Transgenic mice (line 61) overexpressing a protein (hAsyn) have been shown to This is an animal model of Parkinson's disease (PD) that has been used in Accumulation of hAsyn and serine 129 in the cortical and subcortical brain regions, including the substantia nigra, The aggregation and deposition of phosphorylated hAsyn (pser129-Asyn) in ockenstein E et al. (2002) J. Neurosci. Res. 68(5): 568-78) and movement disorders, such as lack of coordination, muscle weakness, and impaired balance. The damage is observed at 2-4 months of age (Fleming et al. 2004, J Neurosci 2 4(42):9434-40). The therapeutic effect of the compounds of formula (I) was evaluated by behavioral (motor performance) assessment. Histological examination of the thyroid gland and brain revealed that the thyroid gland aggregated hAsyn (insoluble in the treated animals) was present in the thyroid and brain. Biochemical measurements of aggregated hAsyn and pSer129-Asyn deposits ("active fractions") For this purpose, transgenic strain 61 mice (4 weeks old) and age / Gender-matched non-transgenic littermates were first treated with ART at baseline. Irwin test battery test, rotarod, wire suspension, The Irwin test is used to measure general health. Condition (weight, body temperature, presence of whiskers, hair and eye structure, righting reflex, blinking nerve The wire suspension test and vertical pole test are performed to evaluate the , is performed to detect neuromuscular abnormalities. The rotarod test evaluates motor coordination ability ( The time it takes to fall at a constant speed is measured in rpm / min. , motor coordination and balance (time to cross the beam and number of errors / slips) The pasta chewing test is used to evaluate orofacial motor disorders (the number of chews and chewing time). The animals were administered the compound of formula (I) by oral gavage for 24 weeks to evaluate the frequency of the episodes. During the treatment period, animals were treated twice more at 12 and 24 weeks of treatment. At the end of the treatment period, all mice were placed under deep anesthesia and placed in a stable position. The animals were euthanized and perfused transcardially with saline. The brains were removed and hemisected. The brains were snap frozen on dry ice for biochemical analysis, while the right hemibrain was used for histological evaluation. The right hemibrain was post-fixed in 4% PFA, embedded in a cryomold, and frozen. The treated animals were embedded in T medium and 10 μm cryosections were collected to examine the hippocampus and cortex of the treated animals. The levels of hAsyn and pSer129-Asyn deposition in the spleen were determined by immunohistochemistry. Measure.

[0206] For biochemical analysis of soluble and insoluble hAsyn, 10 volumes of flash-frozen hemibrains were used. Cell lysis buffer [20 mM Tris-HCl, pH 7.4, 50 mM NaCl , 1% Triton X-100, 0.2mM sodium orthovanadate, protein Homogenize in a phospholipase inhibitor cocktail and a phosphatase inhibitor cocktail. The mixture was then centrifuged (15,000 g, 60 min, After incubation at 4°C, the supernatant was collected and designated as the "Triton X-100 soluble fraction." The ton X-100 insoluble pellet was washed once in cell lysis buffer and then resuspended in 2% sodium dodecyl sulfate. Resuspend in cell lysis buffer containing sodium dodecyl sulfate (SDS). Collect the resulting homogenate in S and name it "Triton X-100 insoluble fraction." "Triton-X-100 soluble fraction" and "Triton-X-100 insoluble fraction" The levels of human alpha-synuclein present in the "active fraction" were analyzed using MesoScale D. hAsyn Immunosorbent Assay Kit (Cat. No. K15) from Discovery (MSD) Quantitation is by electrochemiluminescence using 1TGD.

[0207] Treatment with a compound of formula (I) 1) reduces histologically the intraneuronal aggregation of pser129-Asyn 2) a decrease in the number of deposits in the "Triton X-100 insoluble fraction" 3) Irwin battery, rotarod, and wire rod Behavioral tests include the yar suspension, beam walk, and / or pasta-grazing test. These studies have shown functional benefits (improved athletic performance) in both groups.

[0208] C. In vivo therapeutic effects on acute glaucoma-induced ischemia-reperfusion (I / R) model: Chen YJ et al. (2015), Invest Ophthalmol.Vis Sc i.56(3):1506-16.

[0209] The efficacy of compounds of formula (I) is evaluated in an acute glaucoma animal model. Male Sprague-Dawley (SD) rats, 8 weeks old, weighing 0.00 g, were housed in a room with a temperature and humidity The animals were housed in a controlled animal room with a 12-hour light / 12-hour dark cycle. and water ad libitum. Animals were allowed to acclimate for one week before any experiment. SD rats The mice were randomly assigned to a control and / or treatment group. Compounds of formula (I) were administered orally (by gavage). Two protocols are considered, in this case acute glaucoma-induced Treatment begins 24 hours before or 1 hour after induction of acute I / R injury.

[0210] 50 mg / kg ketamine and 2 mg / kg xylazine to induce I / R injury Induce general anesthesia by intraperitoneal injection of a mixture of 0.5% saline and topical corneal analgesic. Proparacaine acetate eye drops were administered in drops, and pupil dilation was achieved with 0.5% tropicamide and After analgesia and pupil dilation, a small amount of ocular At 150 cm above the cannula, insert a 30-gauge needle connected to a saline reservoir. The retinal ischemia was detected by the fundus. The cannulation is continued for 60 minutes. After removing the injection needle from the anterior chamber, OP returns to normal. Antibiotic ophthalmic gel containing tobramycin is applied to the eye before and after the procedure. The rats were sacrificed 7 days after I / R injury to determine the effect of treatment with the compound of formula (I). Long-term effects are observed. After harvest, retinal thickness is examined by histological staining (Mayer et al., 2004). P,(1896),Mitt.zool.Stn.Neapel.,12,303). The number of retinal ganglion cells is also quantified by immunohistochemistry. Retinal function is assessed 7 days after I / R injury by electroretinogram (ERG).

[0211] Treatment with a compound of formula (I) resulted in: 1) a reduction in retinal thickness as measured by H&E staining; 2) showed an increase in the number of retinal ganglion cells stained by immunohistochemistry 3) retinal imaging by analyzing various electrical responses obtained by electroretinography. The function has been improved.

[0212] D. In vivo therapeutic effects on kainic acid-induced temporal lobe epilepsy (TLE) model Sanchez et al. (2019) Neurobiology of Disease 1 24:531-543.

[0213] Compounds of formula (I) are evaluated in a kainate-induced seizure rat model. Wee-Dawley rats were intraperitoneally injected with kainate (10 mg / kg) to induce seizures. Treatment is by intracavitary injection or with saline as a vehicle control. The severity of behavioral seizures after kainate injection was assessed using the Racine scale (Racine RJ(1972).Electroencephalogr.Clin.Neur According to the Ophysiol.32(3),269-279, the following was graded as mild (score Scored from 1 to more severe (score 5): 1) Oral and facial clonus and pointing head; 2) clonic convulsions of one forelimb; 3) bilateral forelimb clonus; 4) forelimb clonus and 4) Forelimb clonus with rising and falling. Status epilepticus ( The occurrence of SE was defined as the period from kainate injection to 4 hours of continuous seizure activity (Racine score). Four weeks after administration of kainate, the animals underwent dura mater. After 5 weeks of Kainert administration, the subjects underwent EEG surgery for surface electrode implantation. The EEG is recorded for 24 hours. The animals are then treated with a compound of formula (I) every three consecutive days. They receive a daily dose (oral gavage) during which their brain activity is monitored by EEG recording. After 96 hours (4 days) of baseline, animals are terminally sacrificed.

[0214] Treatment with compounds of formula (I) reduced epileptic activity in treated animals, as evidenced by EEG. determined by a decrease in seizure number, seizure duration, or interictal spike frequency. Characterized (Sanchez et al. (2019) Neurobiology of Di sease 124:531-543).

[0215] E. Compounds of Formula (I) on the hTauP301L-Tg Mouse Model of Tauopathy In vivo effects of The hTauP301L-Tg model used in this study included the brainstem, midbrain, and more Tau hyperphosphorylation (AT8 and AT1) in the cortex and hippocampus, although to a lesser extent 00) indicates an age-dependent neuronal tauopathy characterized by Hyperphosphorylated tau exhibits conformational changes that lead to tau aggregation, and mice from 6 months of age As a result of the pathological condition, these mice develop neurofibrillary tangles. They develop progressive motor disorders such as grasping behavior accompanied by rhesus pylori, leading to early death at 8-11 months of age (re MYND, unpublished data; Terwel et al., 2005).

[0216] Treatment of hTauP301L-Tg mice with the compound of formula (I) has the following effects: 1) on survival rate; 2) showed significant benefit in motor function (grasping behavior, beam movement) work), 3) reduced the severity of neuropathology, and 4) in the insoluble fraction of brain tissue samples. This reduces the levels of aggregated and / or hyperphosphorylated tau.

[0217] Example 4: Preparation of unit dosage form (preparation, DP) A. Description and Preparation of Capsules of Compound (I) The compounds of formula (I) may be formulated as immediate release capsules. , 100 mg of compound in a size 00 Swedish orange hard gelatin capsule ( It is a dry blend containing 1) (free base equivalent). The qualitative and quantitative composition is shown. Shown in 1.

[0218] [Table 1]

[0219] Compound (I) has suitable physical, biopharmaceutical and pharmacokinetic properties for the development of an immediate release capsule formulation. It is a drug substance with the following characteristics and chemical properties. It is reasonably stable. It is filled into capsules. The blended powder contains common excipients, namely, microcrystalline cellulose, croscarmellose, and Contains thorium, colloidal silicon dioxide and magnesium stearate. The functions and properties of these excipients are summarized in Table 1. All components were formulated to the concentrations typical for solid oral dosage forms. The selection of excipients for the capsule powder was based on compatibility studies and short-term stability studies. These studies did not indicate any incompatibilities with the selected excipients.

[0220] To prepare the powder blend, the excipients and active ingredients are sieved before use. Microcrystalline cellulose, Compound (I) and colloidal silicon dioxide were mixed. The blend was Sieve, add the remaining microcrystalline cellulose, and homogenize the batch while mixing. Magnesium stearate was added to the blend and homogenized again.

[0221] For encapsulation, the blend was placed into size 00 gelatin capsules using an encapsulation device. The capsules were filled into a cell. Dust was removed from the capsules, the weight was sorted, and the capsules were placed in HDPE bottles. According to the same procedure as above, capsules containing the compound of formula (I) at various strengths were filled into the capsules. A capsule was prepared.

[0222] How to monitor dissolution rate by HPLC Dissolution by HPLC Methods for monitoring dissolution rate have been established. Dissolution conditions are as follows:

[0223] [Table 2]

[0224] Peak retention time: The peak corresponding to the compound of formula (I) elutes at approximately 2.1 minutes. The dissolution profile of the drug can be seen in Figure 6.

[0225] B. Description and preparation of film-coated tablets of Compound (I) For example, one tablet of Compound (I) contains 300 mg of Compound (I) (free base equivalent). The manufacturing unit operation that gives the formulated DP is It may involve aqueous wet granulation followed by tableting and aqueous film coating processes. The qualitative and quantitative composition is shown in Table 2 below.

[0226] [Table 3]

[0227] Compound (I) is a compound for the development of an immediate release oral DP formulation manufactured by conventional techniques. A drug substance that has suitable physical, biopharmaceutical and chemical properties. It is reasonably stable. The final DP contains the following excipients for the tablet core: microcrystalline cellulose, povidone croscarmellose sodium, copovidone, anhydrous silica colloid and fumaric acid sodium Sodium tearyl. Consists of hypromellose, macrogol, titanium dioxide and iron oxide. The core tablets were sprayed with a water-based film coat consisting of the following: The compositions and properties are shown in Table 2. All ingredients were used in amounts typical for oral solid dosage forms. The selection is further supported by compatibility studies of binary mixtures of the major components and short-term stability studies. It was.

[0228] Typical batch formulation for an active batch of approximately 8,000 film-coated tablets As shown in Table 3 below.

[0229] [Table 4]

[0230] The various steps of the manufacturing process are described below.

[0231] Granulation process Compound (I) (HCl salt), microcrystalline cellulose, and a portion of povidone are batch blended Accurately weigh and sieve the mixture according to the instructions, and mix it in a high-shear mixer granulator with an appropriate bowl size for 5-1 Mix for 5 minutes.

[0232] · Determination of loss on drying and bulk density (starting reported values ​​before wet agglomeration).

[0233] Prepare the granulation solution by dissolving povidone in purified water until a translucent solution is obtained. do.

[0234] Adding the granulating solution (i.e., wet granulation) to the dry blend while simultaneously increasing the moisture content The granules are continuously mixed and chopped. The granulation time is at least 1 hour after all the granulation solution has been added. It also takes 3 minutes.

[0235] Sift the wet granules through a 3.0 mm mesh sieve.

[0236] The sieved wet granules are dried in a drying oven under the following conditions: Objective: respectively Loss on drying of 3.5% or less for the active formulation and 4.5% or less for the placebo formulation Temperature: 50-60°C. In-process control: Loss on drying: Target: 3.5% or less (active matter) , 4.5% or less (placebo).

[0237] · Pass the dried granules through a 1.4 mm mesh sieve.

[0238] Drying loss at the same specifications and additional IPC (bulk density and tap density, flowability) Repeat the volume measurement.

[0239] If granules are produced in sub-batches, mix the fractions in a gravity blender for 10 minutes. The bulk density, tapped density, flowability and loss on drying of IPC under the same specifications were repeatedly measured. return.

[0240] Determine yield.

[0241] Compressed mass mixing If necessary, adjust the amount of intergranular phase to suit the granule yield.

[0242] Croscarmellose sodium and silicon dioxide are passed through a 1.4 mm mesh sieve. The granules are sieved through a sieve directly into the stainless steel drum containing the sieved dried granules.

[0243] ·Gravity mixing Goal: Mixing time: 8-15 minutes. Goal: Mixer speed: 20-30 rpm.

[0244] Sieve the sodium stearyl fumarate through a 0.8 mm mesh sieve. Place directly into a stainless steel drum.

[0245] ·Gravity mixing Goal: Mixing time: 3 minutes.

[0246] Goal: Mixer speed: 20-30 rpm.

[0247] In-process control of compacted mass: Loss on drying: Target: 4.0% or less (active formulation) and 4.5% or less (placebo formulation) . ○Liquidity target: Free liquidity.

[0248] Tableting Process · Compress the final compacted mass into core tablets.

[0249] Tablet core parameters: Mass: Target: 550.0mg±5% (522.5~577.5mg) Length: Target: 16.6mm + 0.2mm (16.6~16.8mm) Width: Target: 7.4mm+0.2mm(7.4~7.6mm) Height: Target: 5.2~5.8mm Crushing resistance: Target: 140N or more Friability: Target: Maximum 1.0% Disintegration time: Target: 15 minutes or less Core dust removal and yield calculation Coating of Compound (I) (HCl salt) tablets Stir the purified water with a propeller stirrer to form a vortex, then add the coating compound ( Add Aquapolish® and stir the suspension at high speed for 15 minutes. , then reduce speed and stir for an additional 45 minutes.

[0250] Place the remaining purified water in a suitable beaker and gradually add the iron oxide while homogenizing. For example, Ultra Turrax) and continue for about 30 minutes.

[0251] Add this dispersion to the continuously stirring polymer solution and continue stirring for approximately 30 minutes. Afterwards, the final suspension is passed through a 0.5 mm sieve.

[0252] The tablet cores are transferred to a drum coater and heated with intake air (drum coater speed: interval) . ○Product temperature: Target: 35~45℃ The suspension is stirred with a propeller stirrer during the coating process, and the automatic spraying process Apply by. ○Product temperature: Target: 35~45℃ Spray air pressure: Target: 1.6-2.0 bar Relative spray rate: Target: Maximum 3.5g / min / kg Coat the tablet cores until the final desired weight is achieved.

[0253] Film-coated tablet parameters: Appearance: Light pink, oblong with no notches ○Mass: Target: 583.0mg±5% (553.9~612.2mg) Length: Target: 16.6mm + 0.3mm (16.6~16.9mm) ○Width: Target: 7.4mm+0.3mm(7.4~7.7mm) Height: Target: 5.4-6.0mm (active substance), reported value (placebo) Weight gain: Approximately 33.0 mg / tablet -Operate the drum coater in interval mode for approximately 40 minutes with an intake air temperature of approximately 30°C. , and dry the film-coated tablets.

[0254] All final product batches are packed in tightly sealed containers with double PE inside liners containing desiccant between the liners. Store in tightly sealed stainless steel drums.

[0255] Following the same procedure as above, tablets containing various strengths of the compound of formula (I) were prepared. .

[0256] How to monitor dissolution rate by HPLC A method for monitoring the dissolution rate has been established. The dissolution conditions are as follows: , n=6 subjects will be tested in each run.

[0257] [Table 5]

[0258] Peak retention time: The peak corresponding to the compound of formula (I) elutes at approximately 1.2 minutes. The dissolution profile can be seen in FIG.

[0259] Example 5: Phase 1 Clinical Trial All unit dosage forms used in the clinical trials described below were manufactured according to Example 4. Ta.

[0260] Safety of single and multiple oral doses of the compound of formula (I) in healthy adults and elderly people A randomized, double-blind, placebo-controlled study to assess efficacy, tolerability, pharmacokinetics, and food effects Phase 1 study The study involved healthy male and female (non-reproductive potential) volunteers aged 18-80 years. A single-center, randomized, placebo-controlled, single- and multiple-ascending-dose study in Lantier The objectives of the study were safety, tolerability, food effect, and pharmacokinetics. After identifying a safe and tolerable single dose in 5-year-old healthy male subjects, the effect of food was assessed. A separate cohort was administered to evaluate the safety of multiple doses. Tolerability, pharmacokinetics, CSF drug levels, and pharmacodynamics were evaluated in elderly (55-80 years) men and women. was evaluated in healthy non-childbearing female volunteers. (Part) is outlined in the following table:

[0261] [Table 6]

[0262] Pharmacokinetics in humans 1. Single-dose pharmacokinetics Seven increasing dose levels of the compound of formula (I) (20, 4 Single-dose pharmacokinetics of 0, 80, 160, 300, 600, and 1000 mg of hydroxybenzoates were compared in healthy young subjects. A randomized, placebo-controlled, time-lag, parallel / crossover study in young volunteers The pharmacokinetic data of Compound (I) were collected in the blood for up to 72 hours after administration. The pharmacokinetics of Compound (I) was measured in plasma and urine at various dose levels. Rapid absorption, nearly dose-proportional C from 20 to 1000 mg max Increase and average 3. A consistent dose-dependent profile was observed, with terminal half-lives (t1 / 2) ranging from 9 hours to a mean of 10.7 hours. The exposure (AUC over 24 hours) was measured at 300, 600 Dose proportionality was observed at the three highest dose levels of 1000 mg and 1,000 mg. This is suggested by the dose-normalized AUC, which does not deviate by more than about 10% at these dose levels. It is.

[0263] In addition to pharmacokinetic evaluation of escalating doses, an evaluation of the food effect was included in Part 1b of the study. In this case, a separate cohort of 12 healthy elderly subjects was The rats were administered 300 mg of Compound (I) at a dose of 100 mg per day. This was because food was the only source of Compound (I) exposure (AU). C), i.e., approximately 9 times the exposure in the fasting state. 0% was achieved in the fed state. However, absorption was delayed by approximately 3 hours, and Compound (I) C max is the C of compound (I) in the fasting state max reached about 60% of the total. Drug administration of Compound (I) in a cohort of healthy elderly people at 300 mg of Compound (I) in the fasting state Part 1a: Fasting, kinetics of Compound (I) 300 mg in a healthy young adult cohort When compared with the respective values, exposure (AUC) and C max A reasonable difference (i.e., 15% There was no difference in the

[0264] [Table 7] TIFF2026032031000009.tif91166

[0265] In summary, the peak plasma concentration (C max ) and systemic exposure (AUC 0- t and AUC 0-inf ) is a single dose of 20 mg to 1000 mg of compound (I). The T of compound (I) was significantly increased after max Median: 0.50 to 1.50 hours and the equivalent range of individual values ​​for the 20 mg to 1000 mg dose levels (0.50 h The doses of 160 mg, 300 mg, and 1000 mg were associated with side effects ranging from 1.50 to 1.50 hours. Somewhat higher values ​​were observed at dose levels (ranging from 0.50 hours to 3.00 hours). The mean terminal half-life of compound (I) ranged from 4.59 hours to 8.84 hours across seven dose levels. The C of Compound (I) was in the range of 20 mg to 1000 mg. max Regarding Dose proportionality was observed. The AU of Compound (I) was Dose proportionality was observed for C.

[0266] Compound (I) C max In the fed state, the mean blood glucose level was approximately 42.1% lower than in the fasted state. However, the AUC of Compound (I) 0-t and AUC 0-infOverall exposure to Dew was administered at the 300 mg dose level in both the fed and fasted states. were equal.

[0267] A high-fat, high-calorie diet administered with 300 mg of compound (I) max of Reduced by approximately 40% and T max The median time was increased from 1.00 hours to 4.00 hours. , the extent of absorption of Compound (I) compared to the fasting state (AUC 0-t and AUC 0-inf ) had no effect.

[0268] 2. Multiple-dose pharmacokinetics Three escalating dose levels of Compound (I) (100, administered BID, i.e., twice daily) were administered. Multiple-dose pharmacokinetics of 250 and 500 mg of Compound (I) were evaluated in healthy elderly volunteers. The study was conducted in part 2 of a randomized, placebo-controlled, time-lag, parallel-group study in the United States. Day 1: Twice daily (BID) administration. Day 2: No administration. Days 3-11: 9-day B ID administration. Day 12: Administer once in the morning (mid-morning).

[0269] Pharmacokinetic data of Compound (I) were measured in plasma and urine up to 72 hours after administration. The pharmacokinetics of Compound (I) was investigated at various dose levels and after single and multiple doses. Under given conditions, rapid absorption, nearly dose-proportional C at 100-500 mg BID ma x and increased exposure (AUC) and doses ranging from a mean of 3.9 hours to a mean of 10.7 hours. Characterized by a consistent dose-dependent profile with an independent terminal half-life (t1 / 2) (Figure 2).

[0270] The accumulation of Compound (I) plasma concentrations from days 1 to 12 was minimal, and the calculated end-point The half-life (t1 / 2) was consistent, i.e., on days 1 and 12 of the dosing interval. When comparing exposures between days, the accumulation ratios were 1.35 to 1.38.

[0271] [Table 8] TIFF2026032031000011.tif176167TIFF2026032031000012.tif189167

[0272] In summary, Day 1: Compound (I) C max , AUC 12-24 and AUC 0-tau is 100mg, There was a clear increase after BID administration of the 250 mg and 500 mg doses.

[0273] The compound on Day 1 was administered in a dose range of 100 mg BID to 500 mg BID. (I) Peak exposure (C max ) and systemic exposure (AUC 0-tau and AUC 12- 24 ), dose proportionality was observed.

[0274] Day 12: C of compound (I) max , AUC 0-48 and AUC 0-tau 100mg, 25 The increase in the serotonin concentration was evident after multiple BID administration of 0 mg and 500 mg of Compound (I). Ta.

[0275] The dose range of 100 mg BID to 500 mg BID was used to evaluate the efficacy of compound (I) on day 12. ) peak exposure (C max ) and systemic exposure (AUC0-tau and AUC 0-48 ) Dose proportionality was observed for

[0276] 3. Cerebrospinal fluid (CSF) pharmacokinetics The pharmacokinetics of multiple doses of Compound (I) in CSF were investigated in healthy elderly volunteers. Three escalating dose levels of Compound (I) (10 mg / kg bw, administered BID, i.e., twice daily) were administered. Randomized, placebo-controlled, time-staggered, parallel-group study of 0, 250, and 500 mg of Compound (I) The study was conducted using a group test. Day 1: Administration twice a day (BID). Day 2: No administration. Day 3 and Day 11: BID administration for 9 days. Day 12: One dose in the morning.

[0277] Pharmacokinetic data of Compound (I) were measured in CSF up to 72 hours after the final dose. The pharmacokinetics of Compound (I) were investigated at various dose levels and at each Rapid absorption in single and multiple dose conditions, 100-500 mg BID Approximately dose-proportional C max and increased exposure (AUC) and an average of 3.9 hours to average A consistent dose-dependent profile was observed, with a dose-independent terminal half-life (t1 / 2) ranging from 10.7 hours. It is characterized by a profile (Figure 3).

[0278] [Table 9]

[0279] In summary, the CSF PK parameters of Compound (I) were measured at the 100 mg BID dose level. In this study, only one subject could be reported due to insufficient data points. As evidenced by its detection in cSF on day 12 after multiple doses of Compound (I), As can be seen, compound (I) crossed the blood-brain barrier. The CSF-to-plasma ratio for mean systemic exposure was 0.01 at the 250 mg BID dose level. At the 500 mg BID dose level, the rates were 2.5% and 3.4%, respectively, and 4. 2% and 4.6%.

[0280] Based on the experimental results described above, the following summary statistics of the steady-state index were determined ("Math ematical Modeling of Pharmacokinetic Dat a”, DWA Bourne, Routledge, 2018).

[0281] [Table 10]

[0282] To determine the relationship between plasma concentrations of Compound (I) and brain target occupancy after a single oral dose , a Phase 1, open-label, positron emission tomography study in healthy subjects O-linked N-acetylglucosaminidase (O-GlcNAcase) enzyme profiling in human brain Prevalence of selective radiolabels used as positron emission tomography (PET) tracers Quantitation by competitive displacement of O-GlcNAcase inhibitors by compounds of formula (I) PET tracers are typically labeled as radioactive atoms. 18 F or 12 Contains C It is possible. 18 F]-radiolabeled as a selective O-GlcNAcase inhibitor [ 18 F]-LSN3316612 (but not limited to this) can be selected. Therefore, it is important to quantify O-GlcNAcase enzymes in the brain in preclinical studies. exhibiting suitable selectivity and pharmacokinetics as a PET tracer for chemoradiotherapy and human studies This is because it has been shown that (Paul S. et al. (2019) J. Nucl. Med. 60:129-134).

[0283] The primary objective of this study was to determine the effect of Compound (I) on the 18 F]-LSN3316 612Positron emission tomography (PET) was used to measure brain O-GlcNAcase occupancy. The secondary objective was to determine the effect of Compound (I) on the urinary function of the rats after a single oral administration. 18 F]-LSN3 316612 Using PET, the plasma concentration of compound (I) and brain O-GlcNAcase occupancy were evaluated. The purpose of this study was to determine the relationship between the time course of the effect of steroids on the body and the risk of heart failure. PET imaging data were acquired and analyzed. Each subject had a baseline PET scan. PET scans were performed after both doses. O-GlcNAcase receptor occupancy was assessed. The rate was measured at approximately 7 hours or 28 hours after oral administration of Compound (I) (in the range of 100 to 1000 mg). The corresponding estimates of occupancy ranged from 17 to 98%. As shown, a single dose of Compound (I) demonstrated significant receptor occupancy compared to baseline. .

[0284] The relationship between the plasma concentration of compound (I) and O-GlcNAcase was evaluated using a simple saturation model. Well presented, EC 50 was 84.1ng / ml (95% confidence interval: 68.0-100.1 ng / ml) (Figure 5). was achieved.

[0285] Example 6: Phase 2 Clinical Trial Clinical Study Protocol: Efficacy and Safety of Compounds of Formula (I) for the Treatment of Progressive Supranuclear Palsy A randomized, double-blind, placebo-controlled study to evaluate efficacy and safety All unit dosage forms used in the clinical trials described below were manufactured according to Example 4. Ta.

[0286] Primary Objective: To evaluate the safety and tolerability of two different doses of Compound (I) in the treatment of PSP. To evaluate tolerability compared with placebo.

[0287] Secondary Objectives: To evaluate: Pharmacokinetic (PK) parameters of compound (I) Brain tau burden MRI assessment of global and regional midbrain atrophy Biomarker changes in plasma and cerebrospinal fluid (CSF) Ability to perform daily activities Clinical status of the subject Quality of life Cognitive impairment Study Design: This is a study to evaluate the efficacy and safety of compound agonist therapy in patients with suspected PSP Richardson syndrome. A randomized, multicenter, double-blind, placebo-controlled study to study the safety and tolerability of compound (I). This was a controlled trial. Approximately 40 patients (aged 40 to 85 years) were randomly assigned to receive 300ml of Randomize to receive 150 mg or 150 mg or placebo TID PO (with food).

[0288] All subjects were screened to determine eligibility within 6 weeks prior to treatment. Eligible patients will receive the study drug (Compound (I) or placebo) for approximately 12 weeks. Safety and tolerability data will be collected during required study site visits. Also, "home visits" for safety assessments and blood sampling will be arranged. After completion of the treatment period, there will be a 52-week open-label extension period. Subjects who demonstrate adequate adherence to study treatment are eligible for seamless transition to the open-label extension study. It is a rank.

[0289] Test product, dose and administration method: 300 mg or 150 mg of Compound (I) per day Three doses will be administered orally (PO) or a matching placebo.

[0290] Primary safety endpoint: Treatment-emergent events recorded in the three treatment groups at week 12 Frequency of adverse events Exploratory Efficacy Endpoints: Change from baseline scores on the following assessments: PSP Rating Scale (PSPRS) (28-item scale) PSPRS subscale (10-item scale) Corticobasal Ganglionic Function Scale (CBFS) PSP Functional Disability Scale (PSPFDS) Schwab and England Activities of Daily Living (SEADL) Clinical Global Impression of Change (CGI-C) Progressive Supranuclear Palsy Quality of Life Scale (PSP-QoL) Montreal Cognitive Assessment (MoCA) Dimensional Apathy Scale (DAS) Color Trails Exam Part 1 and 2 (CTT-1 and CTT-2) ·Letter fluency test Changes from baseline in the following parameters: Neurodegenerative and neuroinflammatory CSF biomarkers, e.g., neurodegeneration panel: total tau, p -Tau, NfL and neuroinflammation panels Whole brain volume measured by brain volumetric MRI Regional (midbrain, frontal lobe, third ventricle) volumes measured by brain volumetric MRI Plasma and CSF (NfL, total tau, p-tau) concentrations Safety Endpoints: Treatment-emergent adverse events (TEAEs) Serious Adverse Events (SAEs) Electrocardiogram (ECG) Clinical laboratory measurements Columbia-Suicide Severity Rating Scale (C-SSRS) Statistical analysis: Analysis Population: The complete analysis set includes all randomized patients. The safety set includes patients who were randomized to the compound ( All patients receiving at least one dose of I) are included. , including all patients who completed the study without major protocol deviations.

[0291] The preferred dosing regimen for Compound (I) is particularly safe and well tolerated.

[0292] Example 7: Phase 2 Clinical Trial, Extended Dosing The study design of this Example 7 is to evaluate the efficacy and safety of PSP in patients suspected of having Richardson syndrome. A randomized, multicenter, double-blind, prospective study to study the safety and tolerability of compound (I) This is a placebo-controlled study similar to that described in Example 6. Approximately 40 patients ( (40 to 85 years old) in a 2:1:1:1 ratio of 300 mg, 150 mg, or 75 Patients will be randomized to receive 1 mg or placebo TID PO (with or without food).

[0293] The preferred dosing regimen for Compound (I) is particularly effective, safe, and well tolerated. A dose of 75 mg TID may be used for patients who cannot tolerate higher doses. .

[0294] Example 8: Randomized, double-blind study of Compound (I) for the treatment of progressive supranuclear palsy (PSP) Placebo-controlled Phase 2 study

[0295] [Table 11] TIFF2026032031000016.tif245170TIFF2026032031000017.tif101170

[0296] The studies have shown that the preferred dosing regimen for Compound (I) is particularly effective and safe. and is well tolerated.

[0297] References Boxer AL, Lang AE, Grossman M, et al. Davunetide in patients with progressive supranucle ar palsy:a randomised,double-blind,place bo-controlled phase 2 / 3 trial.Lancet Neu rol.2014;13(7):676-85. Hoglinger GU, Respondek G, Stamelou M et al. (20 17)Clinical diagnosis of progressive sup ranuclear palsy:The movement disorder so ciety criteria.Mov Disord.a;32:853-64. Hoglinger GU, Schope J, Stamelou M, Kassub ek J, Del Ser T, Boxer AL et al. (2017) Longitudin. al magnetic resonance imaging in progres sive supranuclear palsy:A new combined s core for clinical trials.Mov Disord.32(6 ):842-52. Stamelou M,Schope J,Wagenpfeil S,Del Se r T,Bang J,Lobach IY,Luong Pら(2016)Power calculations and placebo effect for fut ure clinical trials in progressive supra nuclear palsy.Mov Disord.31(5):742-7. Tolosa E,Litvan I,Hoglinger GUら(2014)A phase 2 trial of the GSK-3 inhibitor tid eglusib in progressive supranuclear pals y.Mov Disord.29(4):470-8. Wahlund LO,Barkhof F,Fazekas Fら(2001)A new rating scale for age-related white m atter changes applicable to MRI and CT.S troke.32(6):1318-22.

Claims

1. A compound of formula (I) for use in a method of treating a human subject 【Chemistry 1】 and / or a tautomer thereof, wherein the method comprises the step of: or one or more unit dosage forms containing a tautomer thereof, and / or its tautomers to a plasma concentration of at least about 35 ng / mL at trough. The compound of formula (I) as defined above, including repeated administration at a dose and daily administration frequency sufficient to maintain and / or tautomers thereof.

2. The plasma concentration of the compound of formula (I) and / or its tautomer is about 45n 2. The compound for use according to claim 1, wherein the concentration of erythritol in the blood is maintained in the range of 2000 to 2000 ng / mL. and / or its tautomers.

3. A compound of formula (I) for use in a method of treating a human subject 【Chemistry 2】 and / or a tautomer thereof, wherein the method comprises the step of: or one or more unit dosage forms containing the tautomer thereof, (I) and / or its tautomers to a mean plasma concentration of at least about 155 ng / mL, and at a dose and daily dosing frequency sufficient to maintain A compound of formula (I) and / or a tautomer thereof.

4. The mean plasma concentration of the compound of formula (I) and / or its tautomers over a 24-hour period The use according to claim 3, wherein the blood glucose concentration is maintained in the range of about 270 ng / mL to about 2000 ng / mL. and / or tautomers thereof.

5. A compound of formula (I) for use in a method of treating a human subject 【Transformation 3】 and / or a tautomer thereof, wherein the method comprises the step of: or one or more unit dosage forms containing a tautomer thereof at a concentration of about 1650 to about 7390 ng / mL Maintaining the plasma Cmax of the compound of formula (I) and / or its tautomers at steady state The compound of formula (I) is administered in a dose and at a daily administration frequency sufficient to and / or tautomers thereof.

6. A compound of formula (I) for use in a method of treating a human subject 【Chemistry 4】 and / or a tautomer thereof, wherein the method comprises the step of: or one or more unit dosage forms containing the tautomer thereof, ＊ h / mL of the compound of formula (I) and / or its tautomer over 24 hours This includes repeated administration at a dose and daily frequency sufficient to maintain the patient in a steady state. Include compounds of formula (I) above and / or tautomers thereof.

7. Use of the compound of formula (I) and / or its tautomers administered at the daily dosing frequency described above.

7. Any of claims 1 to 6, wherein the amount is administered orally and ranges from about 150 mg to about 500 mg.

1. A compound and / or a tautomer thereof for use according to claim 1.

8. The compound of formula (I) and / or its tautomer has a plasma Cmax of about 3580 to about 73 90 ng / mL of the compound and / or its tautomer for use according to claim 5. body.

9. The compound of formula (I) and / or its tautomer has a plasma AUC of about 3 over 24 hours. 0150~about 90500ng ＊ h / mL of the compound for use according to claim 6. and / or its tautomers.

10. Use of the compound of formula (I) and / or its tautomers administered at the daily dosing frequency described above.

10. Any of claims 1 to 9, wherein the amount is administered orally and ranges from about 300 mg to about 500 mg.

1. A compound and / or a tautomer thereof for use according to claim 1.

11. the repeated administration dose of the compound of formula (I) and / or its tautomer remains constant; A compound and / or a tautomer thereof for use according to any one of claims 1 to 10. 。

12. The daily administration frequency of the compound of formula (I) and / or its tautomer is twice a day or once a day. 3 times the compound and / or its use according to any one of claims 1 to 11. Tautomer of.

13. When a daily dose of a compound of formula (I) and / or its tautomer is administered orally, The dosage according to any one of claims 1 to 12 is about 240 mg to about 1500 mg per day. Compound and / or tautomer thereof for use.

14. About 150 mg three times a day, or about 250 mg twice a day, or about 300 mg once a day 3 times a day, or about 500 mg of a compound of formula (I) and / or a tautomer thereof, twice a day 14. The compound for use according to any one of claims 1 to 13, comprising administering an oral dose of and / or its tautomers.

15. An increase in a human subject suffering from or developing a disease or condition. The compound and / or compound for use according to any one of claims 1 to 14, which has a risk of or its tautomer.

16. 16. The use of claim 15, wherein the disease or condition is selected from one or more proteinopathies. and / or tautomers thereof.

17. The disease or condition is a neurological or neurodegenerative disease, sleep disorder, neuropsychiatric condition, diabetes, or cancer 17. The compound for use according to claim 15 or 16, selected from the group consisting of cardiovascular disease and stroke. and / or tautomers thereof.

18. The disease or condition is one or more of tauopathy, synucleinopathy, and Alzheimer's disease. Disease, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis with cognitive impairment, argyrophilic granulomatosis, behavioral disorder frontotemporal dementia al dementia), non-fluent and semantic variant primary progressive aphasia (non- fluent and semantic variant primary prog Resistive aphasia, Bluit disease, Corticobasal degeneration, dementia pugilistica, dementia with Lewy bodies, diffuse neurofibrillary stenosis with calcification Diffuse neurofibrillary tangles with deficiency, Down's syndrome, familial British dementia, familial Danish dementia FGD, frontotemporal dementia with parkinsonism linked to chromosome 17 (FGD) rontotemporal dementia with parkinsonism linked to chromosome 17), frontotemporal lobar degeneration, glioma, Ganglioneuroma, Gerstmann-Sträussler-Scheinker disease, globular glial tauopathy Chi, Guadeloupe Parkinsonism, Hallervorden-Spatz disease, lead encephalopathy, Lipov Stenosis, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick syndrome Pallidopontonigral degeneration (Pallidopontonigral degene) ration), Parkinson's disease, Parkinson's disease dementia, Parkinsonism in Guam Dementia syndrome, Pick's disease, postencephalitic parkinsonism, prion disease, fatal familial insomnia, - Lew's disease, progressive supercortical gliosis gliosis), progressive supranuclear palsy, pure autonomic failure, Richardson's syndrome , subacute sclerosing panencephalitis, tangle-only dementia, tuberous sclerosis dementia, Huntington's disease or mild cognitive impairment, chronic traumatic encephalopathy, primary progressive aphasia, progressive Non-fluent aphasia, semantic dementia, Steele-Richardson-Olszewski syndrome Group, epilepsy, chronic and acute inflammation, Crohn's disease, neuroinflammation, subarachnoid hemorrhage, multiple sclerosis ataxia, Friedreich's ataxia and adrenoleukodystrophy, Item 15, 16 or 17, a compound for use and / or its derivatives. Mutant.

19. The compounds and / or their tautomers may be pharmaceutically acceptable solvates and / or The compound for use according to any one of claims 1 to 18 is administered in the form of a salt. and / or its tautomers.

20. 20. The method of claim 19, wherein the compound and / or its tautomer is administered in the form of its hydrochloride salt. The compound and / or its tautomer for use as described above.

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