WO2021094312A1 - Composés inhibiteurs d'oga contenant de la pyrrolidine et de la bicyclohétéroaryle - Google Patents

Composés inhibiteurs d'oga contenant de la pyrrolidine et de la bicyclohétéroaryle Download PDF

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WO2021094312A1
WO2021094312A1 PCT/EP2020/081646 EP2020081646W WO2021094312A1 WO 2021094312 A1 WO2021094312 A1 WO 2021094312A1 EP 2020081646 W EP2020081646 W EP 2020081646W WO 2021094312 A1 WO2021094312 A1 WO 2021094312A1
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disease
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José Manuel Bartolomé-Nebreda
Andrés Avelino TRABANCO-SUÁREZ
Ana Isabel De Lucas Olivares
Sergio-Alvar Alonso-De Diego
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Janssen Pharmaceutica Nv
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to O-GlcNAc hydrolase (OGA) inhibitors, having the structure shown in Formula wherein the radicals are as defined in the specification.
  • OGA O-GlcNAc hydrolase
  • the invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which inhibition of OGA is beneficial, such as tauopathies, in particular Alzheimer’s disease or progressive supranuclear palsy; and neurodegenerative diseases accompanied by a tau pathology, in particular amyotrophic lateral sclerosis or frontotemporal lobe dementia caused by C90RF72 mutations; or alpha synucleinopathies, in particular Parkinson’s disease, dementia due to Parkinson’s (or neurocognitive disorder due to Parkinson’s disease), dementia with Lewy bodies, multiple system atrophy, or alpha synucleinopathy caused by Gaucher’s disease.
  • tauopathies in particular Alzheimer’s disease or progressive supranu
  • O-GlcNAcylation is a reversible modification of proteins where N-acetyl-D- glucosamine residues are transferred to the hydroxyl groups of serine- and threonine residues yield O-GlcNAcylated proteins. More than 1000 of such target proteins have been identified both in the cytosol and nucleus of eukaryotes. The modification is thought to regulate a huge spectrum of cellular processes including transcription, cytoskeletal processes, cell cycle, proteasomal degradation, and receptor signalling.
  • O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA) are the only two proteins described that add (OGT) or remove (OGA) O-GlcNAc from target proteins.
  • OGA was initially purified in 1994 from spleen preparation and 1998 identified as antigen expressed by meningiomas and termed MGEA5, consists of 916 amino (102915 Dalton) as a monomer in the cytosolic compartment of cells. It is to be distinguished from ER- and Golgi-related glycosylation processes that are important for trafficking and secretion of proteins and different to OGA have an acidic pH optimum, whereas OGA display highest activity at neutral pH.
  • the OGA catalytic domain with its double aspartate catalytic center resides in the N- terminal part of the enzyme which is flanked by two flexible domains.
  • the C-terminal part consists of a putative HAT (histone acetyl transferase domain) preceded by a stalk domain. It has yet still to be proven that the HAT-domain is catalytically active.
  • OGT O-GlcNAcylated proteins as well as OGT and OGA themselves are particularly abundant in the brain and neurons suggesting this modification plays an important role in the central nervous system. Indeed, studies confirmed that 0-GlcNAcylation represents a key regulatory mechanism contributing to neuronal communication, memory formation and neurodegenerative disease. Moreover, it has been shown that OGT is essential for embryogenesis in several animal models and ogt null mice are embryonic lethal. OGA is also indispensible for mammalian development. Two independent studies have shown that OGA homozygous null mice do not survive beyond 24-48 hours after birth. Oga deletion has led to defects in glycogen mobilization in pups and it caused genomic instability linked cell cycle arrest in MEFs derived from homozygous knockout embryos. The heterozygous animals survived to adulthood however they exhibited alterations in both transcription and metabolism.
  • Oga heterozygosity suppressed intestinal tumorigenesis in an A pc- mouse cancer model and the Oga gene (MGEA5) is a documented human diabetes susceptibility locus.
  • O-GlcNAc-modifications have been identified on several proteins that are involved in the development and progression of neurodegenerative diseases and a correlation between variations of O-GlcNAc levels on the formation of neurofibrillary tangle (NFT) protein by Tau in Alzheimer’s disease has been suggested.
  • O-GlcNAcylation of alpha-synuclein in Parkinson’s disease has been described (Levine, PM, et al. PNAS January 29, 2019, Vol. 116, No. 5, pp 1511-1519; Lewis, YE et al. ACS Chem Biol. 2017 Apr 21, Vol. 2, No. 4, pp 1020-1027; Marotta, NP et al. Nat Chem. 2015 Nov, Vol. No. 11, pp. 913-20).
  • tau is encoded on chromosome 17 and consists in its longest splice variant expressed in the central nervous system of 441 amino acids. These isoforms differ by two N-terminal inserts (exon 2 and 3) and exon 10 which he within the microtubule binding domain. Exon 10 is of considerable interest in tauopathies as it harbours multiple mutations that render tau prone to aggregation as described below.
  • Tau protein binds to and stabilizes the neuronal microtubule cytoskeleton which is important for regulation of the intracellular transport of organelles along the axonal compartments. Thus, tau plays an important role in the formation of axons and maintenance of their integrity.
  • tau aggregation is either one of the underlying causes for a variety of so called tauopathies like PSP (progressive supranuclear palsy), Down’s syndrome (DS), FTLD (frontotemporal lobe dementia), FTDP-17 (frontotemporal dementia with Parkinsonism- 17), Pick’s disease (PD), CBD (corticobasal degeneration), agryophilic grain disease (AGD), and AD (Alzheimer’s disease).
  • tau pathology accompanies additional neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) or FTLD cause by C90RF72 mutations.
  • tau is post- translationally modified by excessive phosphorylation which is thought to detach tau from microtubules and makes it prone to aggregation.
  • O-GlcNAcylation of tau regulates the extent of phosphorylation as serine or threonine residues carrying O- GlcNAc-residues are not amenable to phosphorylation. This effectively renders tau less prone to detaching from microtubules and reduces aggregation into neurotoxic tangles which ultimately lead to neurotoxicity and neuronal cell death.
  • This mechanism may also reduce the cell-to-cell spreading of tau-aggregates released by neurons via along interconnected circuits in the brain which has recently been discussed to accelerate pathology in tau-related dementias. Indeed, hyperphosphorylated tau isolated from brains of AD-patients showed significantly reduced O-GlcNAcylation levels.
  • OGA inhibitor administered to JNPL3 tau transgenic mice successfully reduced NFT formation and neuronal loss without apparent adverse effects. This observation has been confirmed in another rodent model of tauopathy where the expression of mutant tau found in FTD can be induced (tg4510).
  • Dosing of a small molecule inhibitor of OGA was efficacious in reducing the formation of tau-aggregation and attenuated the cortical atrophy and ventricle enlargement.
  • the O-GlcN Acylation of the amyloid precursor protein (APP) favours processing via the non-amyloidogenic route to produce soluble APP fragment and avoid cleavage that results in the AD associated amyloid-beta (Ab) formation.
  • APP amyloid precursor protein
  • Maintaining O-GlcNAcylation of tau by inhibition of OGA represents a potential approach to decrease tau-phosphorylation and tau-aggregation in neurodegenerative diseases mentioned above thereby attenuating or stopping the progression of neurodegenerative tauopathy-diseases.
  • WO2012/117219 (Summit Corp. pic., published 7 September 2012) describes N-[[5- (hydroxymethyl)pyrrolidin-2-yl]methyl]alkylamide and N-alkyl-2-[5- (hydroxymethyl)pyrrolidin-2-yl]acetamide derivatives as OGA inhibitors.
  • WO2014/159234 (Merck Patent GMBH, published 2 October 2014) discloses mainly
  • WO2016/0300443 (Asceneuron S.A., published 3 March 2016), WO2017/144633 and W02017/0114639 (Asceneuron S.A., published 31 August 2017) disclose 1,4- disubstituted piperidines or piperazines as OGA inhibitors;
  • WO2017/144637 discloses more particular 4-substituted l-[l-(l,3-benzodioxol-5-yl)ethyl]-piperazine; 1-[1 -(2,3- dihydrobenzofuran-5-yl)ethyl]-; l-[l-(2,3-dihydrobenzofuran-6-yl)ethyl]-; and 1-[1- (2,3-dihydro-l,4-benzodioxin-6-yl)ethyl]-piperazine derivatives as OGA inhibitors; WO2017/106254 (Merck Sharp & Dohme Corp.) describes substituted N-[5-[(4- methylene-l-piperidyl)methyl]thiazol-2-yl]acetamide; WO2018/217558 (Eli Lilly and Company) describes 5-methyl-l,3,4-oxadiazol-2-y
  • WO2018/140299 (Eli Lilly and Company) discloses N-[fluoro-5-[[(2S,4S)-2-methyl-4- [(5-methyl-l,2,4-oxadiazol-3-yl)methoxy[-l-piperidyl]methyl]thiazol-2-yl]acetamide as OGA inhibitor.
  • OGA inhibitor compounds with an advantageous balance of properties, for example with improved potency, good bioavailability, pharmacokinetics, and brain penetration, and/or better toxicity profile. It is accordingly an object of the present invention to provide compounds that overcome at least some of these problems.
  • compounds of the present invention have been found to exhibit improved metabolic stability in human and mouse microsomes.
  • the present compounds present a substitution pattern devoid of acetamidothiazole moieties, which can hydrolyse to 2-aminothiazoles, which have been connected to potential toxicities, including genotoxicity (Radice et al. Pharma World 2014 "Mutagenicity evaluation of 2-amino-4-thiazole acetic acid”).
  • R A is selected from the group consisting of a) a six-membered monocyclic heteroaryl radical selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl; b) a five-membered monocyclic heteroaryl radical selected from the group consisting of thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, and oxadiazolyl; and c) a 9- to 10-membered bicyclic heteroaryl radical selected from the group consisting of 1,8-naphthyridinyl, pyrazolo[l,5-a]pyridinyl, imidazo[l,5-a]pyridinyl, imid
  • L A is selected from the group consisting of -0-, -OCH2-, and -CH2O-;
  • R la , R lb , R 2a and R 2b are each independently selected from the group consisting of hydrogen and Ci-3alkyl, in particular methyl; with the proviso that at least one of R la , R lb , R 2a and R 2b is Cmalkyl, in particular methyl;
  • R is H or CH 3 ; and R B is wherein the dashed line represents an optional double bond;
  • R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and fluoro; and the pharmaceutically acceptable salts and the solvates thereof.
  • Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above.
  • An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier.
  • Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
  • Exemplifying the invention are methods of preventing or treating a disorder mediated by the inhibition of O-GlcNAc hydrolase (OGA), comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
  • OAA O-GlcNAc hydrolase
  • An example of the invention is a method of preventing or treating a disorder selected from a tauopathy, in particular a tauopathy selected from the group consisting of Alzheimer’s disease, progressive supranuclear palsy, Down’s syndrome, frontotemporal lobe dementia, frontotemporal dementia with Parkinsonism-17, Pick’s disease, corticobasal degeneration, and agryophilic grain disease; or a neurodegenerative disease accompanied by a tau pathology, in particular a neurodegenerative disease selected from amyotrophic lateral sclerosis or frontotemporal lobe dementia caused by C90RF72 mutations, or preventing or treating a disorder selected from an alpha synucleinopathy, in particular Parkinson’s disease, dementia due to Parkinson’s (or neurocognitive disorder due to Parkinson’s disease), dementia with Lewy bodies, multiple system atrophy, or alpha synucleinopathy caused by Gaucher’s disease, comprising administering to a subject in need thereof, a prophylactically or a therapeutically effective amount of
  • tauopathy in particular a tauopathy selected from the group consisting of Alzheimer’s disease, progressive supranuclear palsy, Down’s syndrome, frontotemporal lobe dementia, frontotemporal dementia with Parkinsonism-17, Pick’s disease, corticobasal degeneration, and agryophilic grain disease; or a neurodegenerative disease accompanied by a tau pathology, in particular a neurodegenerative disease selected from amyotrophic lateral sclerosis or frontotemporal lobe dementia caused by C90RF72 mutations or for use in preventing or treating a disorder selected from an alpha synucleinopathy, in particular Parkinson’s disease, dementia due to Parkinson’s (or neurocognitive disorder due to Parkinson’s disease), dementia with Lewy bodies, multiple system atrophy, or alpha synucleinopathy caused by Gaucher’s disease, in a subject in need thereof.
  • a tauopathy selected from the group consisting of Alzheimer’s disease, progressive supranuclear palsy, Down’s syndrome, frontotemporal
  • the present invention is directed to compounds of Formula (I), as defined herein before, and pharmaceutically acceptable addition salts and solvates thereof.
  • the compounds of Formula (I) are inhibitors of O-GlcNAc hydrolase (OGA) and may be useful in the prevention or treatment of tauopathies, in particular a tauopathy selected from the group consisting of Alzheimer’s disease, progressive supranuclear palsy, Down’s syndrome, frontotemporal lobe dementia, frontotemporal dementia with Parkinsonism- 17, Pick’s disease, corticobasal degeneration, and agryophilic grain disease; or maybe useful in the prevention or treatment of neurodegenerative diseases accompanied by a tau pathology, in particular a neurodegenerative disease selected from amyotrophic lateral sclerosis or frontotemporal lobe dementia caused by C90RF72 mutations; or may be useful in the prevention or treatment of alpha synucleinopathies, in particular Parkinson’s disease, dementia due to Parkinson’s (or neurocognizes.
  • OAA O-G
  • the invention is directed to compounds of Formula (I) as referred to herein, and the tautomers and the stereoisomeric forms thereof, wherein R A is selected from the group consisting of a) a six-membered monocyclic heteroaryl radical selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl; b) a five-membered monocyclic heteroaryl radical selected from the group consisting of thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, and oxadiazolyl; and c) a 9- to 10-membered bicyclic heteroaryl radical selected from the group consisting of 1,8-naphthyridinyl, pyrazolo[l,5-a]pyridinyl, imidazo[l,5-a]pyridin
  • R la , R lb , R 2a and R 2b are each independently selected from the group consisting of hydrogen and Ci-3alkyl, in particular methyl; with the proviso that at least one of R la , R lb , R 2a and R 2b is Ci-3alkyl, in particular methyl;
  • R is H or CFh
  • R B is wherein the dashed line represents an optional double bond; and R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and fluoro; and the pharmaceutically acceptable salts and the solvates thereof.
  • the invention is directed to compounds of Formula (I) as referred to herein, and the tautomers and the stereoisomeric forms thereof, wherein R A is selected from the group consisting of a) a six-membered monocyclic heteroaryl radical selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl; and b) a five-membered monocyclic heteroaryl radical selected from the group consisting of thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, and oxadiazolyl; wherein each of a) or b) may be optionally
  • L A is selected from the group consisting of -0-, -OCH2-, and -CH2O-;
  • R la , R lb , R 2a and R 2b are each independently selected from the group consisting of hydrogen and Ci-3alkyl, in particular methyl; with the proviso that at least one of R la , R lb , R 2a and R 2b is Ci-3alkyl, in particular methyl; R is H or CFh; and
  • R B is wherein the dashed line represents an optional double bond; and R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and fluoro; and the pharmaceutically acceptable salts and the solvates thereof.
  • the invention is directed to compounds of Formula (I) as referred to herein, and the tautomers and the stereoisomeric forms thereof, wherein R A is selected from the group consisting of a) a six-membered monocyclic heteroaryl radical selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl; and b) a five-membered monocyclic heteroaryl radical selected from the group consisting of thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, and oxadiazolyl; wherein each of a) or b) may be optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo; cyano; Ci-4alkyl optionally substituted with 1, 2, or 3 independently selected halo substituents; and Ci-4alkyl
  • L A is selected from the group consisting of -0-, -OCH2-, and -CH2O-;
  • R la , R lb , R 2a and R 2b are each independently selected from the group consisting of hydrogen and Ci-3alkyl, in particular methyl; with the proviso that at least one of R la , R lb , R 2a and R 2b is Ci-3alkyl, in particular methyl;
  • R is H or CFh
  • R B is wherein the dashed line represents an optional double bond; and R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and fluoro; and the pharmaceutically acceptable salts and the solvates thereof.
  • the invention is directed to compounds of Formula (I) as referred to herein, and the tautomers and the stereoisomeric forms thereof, wherein R A is selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, oxadiazolyl and pyrazolo[l,5-a]pyridinyl; each of which may be optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo; cyano; Cmalkyl optionally substituted with 1, 2, or 3 independently selected halo substituents; and Cmalkyloxy optionally substituted with 1, 2, or 3 independently selected halo substituents;
  • L A is selected from the group consisting of -0-, -OCH2-, and -CH2O-;
  • R la , R lb , R 2a and R 2b are each independently selected from the group consisting of hydrogen and Ci-3alkyl, in particular methyl; with the proviso that at least one of R la , R lb , R 2a and R 2b is Cmalkyl, in particular methyl;
  • R is H or CH 3 ;
  • R B is wherein the dashed line represents an optional double bond
  • R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and fluoro; and the pharmaceutically acceptable salts and the solvates thereof.
  • the invention is directed to compounds of Formula (I) as referred to herein, and the tautomers and the stereoisomeric forms thereof, wherein R A is selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, and oxadiazolyl; each of which may be optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo; cyano; Ci4alkyl optionally substituted with 1, 2, or 3 independently selected halo substituents; and Ci- 4alkyloxy optionally substituted with 1, 2, or 3 independently selected halo substituents; L A is selected from the group consisting of -0-, -OCH2-, and -CH2O-;
  • R la , R lb , R 2a and R 2b are each independently selected from the group consisting of hydrogen and Ci-3alkyl, in particular methyl; with the proviso that at least one of R la , R lb , R 2a and R 2b is Ci-3alkyl, in particular methyl;
  • R is H or CH 3 ;
  • R B is wherein the dashed line represents an optional double bond
  • R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and fluoro; and the pharmaceutically acceptable salts and the solvates thereof.
  • the invention is directed to compounds of Formula (I) as referred to herein, and the tautomers and the stereoisomeric forms thereof, wherein R A is selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, and oxadiazolyl; each of which may be optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo; cyano; Ci4alkyl optionally substituted with 1, 2, or 3 independently selected halo substituents; and Ci- 4alkyloxy optionally substituted with 1, 2, or 3 independently selected halo substituents;
  • L A is selected from the group consisting of -0-, -OCH2-, and -CH2O-;
  • R la , R lb , R 2a and R 2b are each independently selected from the group consisting of hydrogen and methyl; with the proviso that at least one of R la , R lb , R 2a and R 2b is methyl;
  • R is H or CFh;
  • R B is wherein the dashed line represents an optional double bond
  • R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and fluoro; and the pharmaceutically acceptable salts and the solvates thereof.
  • the invention is directed to compounds of Formula (I) as described herein, wherein L A is -0-.
  • the invention is directed to compounds of Formula (I) as described herein, wherein L A is -OCH2-.
  • the invention is directed to compounds of Formula (I) as described herein, wherein L A is -CH2O-.
  • the invention is directed to compounds of Formula (I) as referred to herein, and the tautomers and the stereoisomeric forms thereof, wherein R A is selected from the group consisting of pyridyl, pyrimidinyl, and pyrazolyl; each of which may be optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo; cyano; and Ci-4alkyl optionally substituted with 1, 2, or 3 independently selected halo substituents;
  • L A is -0-; R la , R lb , R 2a and R 2b are each independently selected from the group consisting of hydrogen and methyl; with the proviso that at least one of R la , R lb , R 2a and R 2b is methyl; in particular, R la , R lb and R 2a are hydrogen, and R2 b is methyl; R is H or CH3; and
  • R B is wherein the dashed line represents an optional double bond
  • R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and fluoro; and the pharmaceutically acceptable salts and the solvates thereof.
  • the invention is directed to compounds of Formula (I) as described herein, wherein
  • R B is a bicyclic radical of formula (b-1), (b-2) or (b-3) DEFINITIONS
  • Halo shall denote fluoro, chloro and bromo
  • Ci-4alkyl shall denote a straight or branched saturated alkyl group having 1, 2, 3 or 4 carbon atoms, respectively e.g. methyl, ethyl, 1 -propyl, 2-propyl, butyl, 1 -methyl-propyl, 2-methyl- 1 -propyl, 1,1-dimethylethyl, and the like
  • Ci-4alkyloxy shall denote an ether radical wherein Ci-4alkyl is as defined before.
  • L A When reference is made to L A , the definition is to be read from left to right, with the left part of the linker bound to R A and the right part of the linker bound to the pyrrolidinediyl or piperidinediyl ring.
  • L A is, for example, -O-CH2-
  • R A -L A - is R A -0-CH 2 -.
  • substituted in general, whenever the term “substituted” is used in the present invention, it is meant, unless otherwise indicated or is clear from the context, to indicate that one or more hydrogens, in particular 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a selection of substituents from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • subject refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, observation or experiment. As used herein, the term “subject” therefore encompasses patients, as well as asymptomatic or presymptomatic individuals at risk of developing a disease or condition as defined herein.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • prophylactically effective amount means that amount of active compound or pharmaceutical agent that substantially reduces the potential for onset of the disease or disorder being prevented.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • compound of Formula (I) is meant to include the addition salts, the solvates and the stereoisomers thereof.
  • stereoisomers or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.
  • the invention includes all stereoisomers of the compound of Formula (I) either as a pure stereoisomer or as a mixture of two or more stereoisomers.
  • Enantiomers are stereoisomers that are non-superimposable mirror images of each other.
  • a 1 : 1 mixture of a pair of enantiomers is a racemate or racemic mixture.
  • Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. If a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof.
  • the absolute configuration is specified according to the Cahn-Ingold-Prelog system.
  • the configuration at an asymmetric atom is specified by either R or S.
  • Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers.
  • a compound of formula (I) is for instance specified as (R)
  • a compound of formula (I) is for instance specified as E
  • E this means that the compound is substantially free of the Z isomer
  • a compound of formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
  • addition salts of the compounds of this invention refer to non toxic "pharmaceutically acceptable addition salts".
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable addition salts.
  • Suitable pharmaceutically acceptable addition salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable addition salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • acids which may be used in the preparation of pharmaceutically acceptable addition salts include, but are not limited to, the following: acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, capric acid, caproic acid, caprybc acid, cinnamic acid, citric acid, cyclamic acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, beta- oxo-glutaric acid, glycolic acid, hippuric
  • Representative bases which may be used in the preparation of pharmaceutically acceptable addition salts include, but are not limited to, the following: ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, dimethylethanol- amine, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylene-diamine, /V-methyl-glucamine, hydrabamine, 1 //-imidazole.
  • the names of compounds were generated according to the nomenclature rules agreed upon by the Chemical Abstracts Service (CAS) or according to the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC).
  • the compounds according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person.
  • the compounds can be prepared according to the following synthesis methods.
  • the compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of Formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali.
  • An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • the final compounds of Formula (I) can be prepared by reacting an intermediate compound of Formula (II) with a compound of Formula (III) according to reaction scheme (1).
  • the reaction is performed in a suitable reaction-inert solvent, such as, for example, dichloromethane, a metal hydride, such as, for example sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride and may require the presence of a suitable base, such as, for example, triethylamine, and/or a Lewis acid, such as, for example titanium tetraisopropoxide or titanium tetrachloride, under thermal conditions, such as, 0 °C or room temperature, or 140 °C, for example for 1 hour or 24 hours.
  • a suitable reaction-inert solvent such as, for example, dichloromethane
  • a metal hydride such as, for example sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride
  • a suitable base such as, for
  • reaction scheme (2) An intermediate compound of Formula (IV) with a compound of Formula (II) according to reaction scheme (2).
  • the reaction is performed in a suitable reaction-inert solvent, such as, for example, acetonitrile, a suitable base, such as, for example, potassium carbonate, triethylamine or diisopropylethylamine, under thermal conditions, such as, 0 °C or room temperature, or 75 °C, for example for 1 hour or 24 hours.
  • a suitable reaction-inert solvent such as, for example, acetonitrile
  • a suitable base such as, for example, potassium carbonate, triethylamine or diisopropylethylamine
  • reaction scheme (2) all variables are defined as in Formula (I), and wherein halo is chloro, bromo or iodo.
  • reaction scheme (3) An intermediate compound of Formula (II) with a compound of Formula (V) followed by reaction of the formed imine derivative with and intermediate compound of Formula (VI) according to reaction scheme (3).
  • the reaction is performed in a suitable reaction-inert solvent, such as, for example, anhydrous dichloromethane, a Lewis acid, such as, for example titanium tetraisopropoxide or titanium tetrachloride, under thermal conditions, such as, 0 °C or room temperature, for example for 1 hour or 24 hours.
  • a suitable reaction-inert solvent such as, for example, anhydrous dichloromethane, a Lewis acid, such as, for example titanium tetraisopropoxide or titanium tetrachloride, under thermal conditions, such as, 0 °C or room temperature, for example for 1 hour or 24 hours.
  • halo is chloro, bromo or iodo.
  • the compounds of the present invention and the pharmaceutically acceptable compositions thereof inhibit O-GlcNAc hydrolase (OGA) and therefore may be useful in the treatment or prevention of diseases involving tau pathology, also known as tauopathies, and diseases with tau inclusions.
  • diseases include, but are not limited to Alzheimer’s disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex, argyrophilic grain disease, chronic traumatic encephalopathy, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, Down’s syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia and parkinsonism linked to chromosome 17 (caused by MAPT mutations), Frontotemporal lobar degeneration (some cases caused by C90RF72 mutations), Gerstmann-Straussler- Scheinker disease, Parkinson’s disease, Guadeloupean parkinsonism, myotonic dystrophy, neurodegeneration with brain iron accumulation, Niemann-Pick disease,
  • the compounds of the present invention and the pharmaceutically acceptable compositions thereof inhibit O-GlcNAc hydrolase (OGA) and therefore may be also useful in the treatment or prevention of diseases involving an alpha synucleinopathy, in particular Parkinson’s disease, dementia due to Parkinson’s (or neurocognitive disorder due to Parkinson’s disease), dementia with Lewy bodies, multiple system atrophy, or alpha synucleinopathy caused by Gaucher’s disease.
  • OAA O-GlcNAc hydrolase
  • treatment is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease or an alleviation of symptoms, but does not necessarily indicate a total elimination of all symptoms.
  • prevention is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting or stopping of the onset of a disease.
  • the invention also relates to a compound according to the general Formula (I), a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salt thereof, for use in the treatment or prevention of diseases or conditions selected from the group consisting of Alzheimer’s disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex, argyrophilic grain disease, chronic traumatic encephalopathy, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, Down’s syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia and parkinsonism linked to chromosome 17 (caused by MAPT mutations), Frontotemporal lobar degeneration (some cases caused by C90RF72 mutations), Gerstmann-Straussler-Scheinker disease, Guadeloupean parkinsonism, myotonic dystrophy, neurodegeneration with brain iron accumulation, Niemann-Pick disease, type C, non-Guamanian motor neuron disease with neurofibrill
  • the invention also relates to a compound according to the general Formula (I), a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salt thereof, for use in the treatment, prevention, amelioration, control or reduction of the risk of diseases or conditions selected from the group consisting of Alzheimer’s disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex, argyrophilic grain disease, chronic traumatic encephalopathy, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, Down’s syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia and parkinsonism linked to chromosome 17 (caused by MAPT mutations), Frontotemporal lobar degeneration (some cases caused by C90RF72 mutations), Gerstmann-Straussler- Scheinker disease, Guadeloupean parkinsonism, myotonic dystrophy, neurodegeneration with brain iron accumulation, Niemann-Pick disease, type C, non- Guamanian
  • the diseases or conditions may in particular be selected from an alpha synucbnopathy, more in particular a tauopathy selected from the group consisting of Parkinson’s disease, dementia due to Parkinson’s (or neurocognitive disorder due to Parkinson’s disease), dementia with Lewy bodies, multiple system atrophy, and alpha synucleinopathy caused by Gaucher’s disease.
  • a tauopathy selected from the group consisting of Parkinson’s disease, dementia due to Parkinson’s (or neurocognitive disorder due to Parkinson’s disease), dementia with Lewy bodies, multiple system atrophy, and alpha synucleinopathy caused by Gaucher’s disease.
  • Amyloid-positive (Ab+) clinically normal individuals consistently demonstrate evidence of an “AD-like endophenotype” on other biomarkers, including disrupted functional network activity in both functional magnetic resonance imaging (MRI) and resting state connectivity, fluorodeoxyglucose 18 F (FDG) hypometabolism, cortical thinning, and accelerated rates of atrophy.
  • MRI magnetic resonance imaging
  • FDG fluorodeoxyglucose 18 F
  • MCI mild cognitive impairment
  • AD dementia Alzheimer’s scientific community is of the consensus that these Ab+ clinically normal individuals represent an early stage in the continuum of AD pathology.
  • Alzheimer’s disease at a preclinical stage before the occurrence of the first symptoms.
  • All the different issues relating to preclinical Alzheimer’s disease such as, definitions and lexicon, the limits, the natural history, the markers of progression and the ethical consequences of detecting the disease at the asymptomatic stage, are reviewed in Alzheimer’s & Dementia 12 (2016) 292-323.
  • Two categories of individuals may be recognized in preclinical Alzheimer’s disease or tauopathies.
  • Cognitively normal individuals with amyloid beta or tau aggregation evident on PET scans, or changes in CSF Abeta, tau and phospho-tau are defined as being in an “asymptomatic at-risk state for Alzheimer’s disease (AR-AD)” or in a “asymptomatic state of tauopathy”.
  • AR-AD Alzheimer’s disease
  • Individuals with a fully penetrant dominant autosomal mutation for familial Alzheimer’s disease are said to have “presymptomatic Alzheimer’s disease”.
  • Dominant autosomal mutations within the tau-protein have been described for multiple forms of tauopathies as well.
  • the invention also relates to a compound according to the general Formula (I), a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salt thereof, for use in control or reduction of the risk of preclinical Alzheimer’s disease, prodromal Alzheimer’s disease, or tau-related neurodegeneration as observed in different forms of tauopathies.
  • the invention also relates to a compound according to the general Formula (I), a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salt thereof, for use in control or reduction of the risk of prodromal Parkinson’s disease.
  • treatment does not necessarily indicate a total elimination of all symptoms, but may also refer to symptomatic treatment in any of the disorders mentioned above.
  • a method of treating subjects such as warm-blooded animals, including humans, suffering from or a method of preventing subjects such as warm blooded animals, including humans, suffering from any one of the diseases mentioned hereinbefore.
  • Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of a prophylactically or a therapeutically effective amount of a compound of Formula (I), a stereoisomeric form thereof, a pharmaceutically acceptable addition salt or solvate thereof, to a subject such as a warm-blooded animal, including a human.
  • the invention also relates to a method for the prevention and/or treatment of any of the diseases mentioned hereinbefore comprising administering a prophylactically or a therapeutically effective amount of a compound according to the invention to a subject in need thereof.
  • the invention also relates to a method for modulating O-GlcNAc hydrolase (OGA) activity, comprising administering to a subject in need thereof, a prophylactically or a therapeutically effective amount of a compound according to the invention and as defined in the claims or a pharmaceutical composition according to the invention and as defined in the claims.
  • OAA O-GlcNAc hydrolase
  • a method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day.
  • the compounds according to the invention are preferably formulated prior to administration.
  • suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula (I) and one or more additional therapeutic agents, as well as administration of the compound of Formula (I) and each additional therapeutic agent in its own separate pharmaceutical dosage formulation.
  • a compound of Formula (I) and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
  • the present invention also provides compositions for preventing or treating diseases in which inhibition of O-GlcNAc hydrolase (OGA) is beneficial, such as Alzheimer’s disease, progressive supranuclear palsy, Down’s syndrome, frontotemporal lobe dementia, frontotemporal dementia with Parkinsonism- 17, Pick’s disease, corticobasal degeneration, agryophilic grain disease, amyotrophic lateral sclerosis, frontotemporal lobe dementia caused by C90RF72 mutations, Parkinson’s disease, dementia due to Parkinson’s (or neurocognitive disorder due to Parkinson’s disease), dementia with Lewy bodies, multiple system atrophy, or alpha synucleinopathy caused by Gaucher’s disease, said compositions comprising a therapeutically effective amount of a compound according to formula (I) and a pharmaceutically acceptable carrier or diluent.
  • OAA O-GlcNAc hydrolase
  • the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • compositions of this invention may be prepared by any methods well known in the art of pharmacy.
  • a therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • the exact dosage and frequency of administration depends on the particular compound of Formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • the pharmaceutical composition will comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% by weight, more preferably from 0.1 to 50% by weight of the active ingredient, and, from 1 to 99.95% by weight, preferably from 30 to 99.9% by weight, more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • the present compounds can be used for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
  • the compounds are preferably orally administered.
  • the exact dosage and frequency of administration depends on the particular compound according to Formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art.
  • said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • suitable unit doses for the compounds of the present invention can, for example, preferably contain between 0.1 mg to about 1000 mg of the active compound.
  • a preferred unit dose is between 1 mg to about 500 mg.
  • a more preferred unit dose is between 1 mg to about 300 mg.
  • Even more preferred unit dose is between 1 mg to about 100 mg.
  • Such unit doses can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration.
  • a preferred dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.
  • a typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient.
  • the time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.
  • the invention also provides a kit comprising a compound according to the invention, prescribing information also known as “leaflet”, a blister package or bottle, and a container. Furthermore, the invention provides a kit comprising a pharmaceutical composition according to the invention, prescribing information also known as “leaflet”, a blister package or bottle, and a container.
  • the prescribing information preferably includes advice or instructions to a patient regarding the administration of the compound or the pharmaceutical composition according to the invention.
  • the prescribing information includes advice or instruction to a patient regarding the administration of said compound or pharmaceutical composition according to the invention, on how the compound or the pharmaceutical composition according to the invention is to be used, for the prevention and/or treatment of a tauopathy in a subject in need thereof.
  • the invention provides a kit of parts comprising a compound of Formula (I) or a stereoisomeric for thereof, or a pharmaceutically acceptable salt or a solvate thereof, or a pharmaceutical composition comprising said compound, and instructions for preventing or treating a tauopathy.
  • the kit referred to herein can be, in particular, a pharmaceutical package suitable for commercial sale.
  • preferred compounds for use in each are those compounds that are noted as preferred above.
  • Still further preferred compounds for the compositions, methods and kits are those compounds provided in the non-limiting Examples below.
  • m.p.” means melting point
  • min means minutes
  • aq.” means aqueous
  • d means day
  • DIPE means diisopropyl ether
  • DMA means N,N- dimethylacetamide
  • r.t.” or RT means room temperature
  • rac or “RS” means racemic
  • SFC means supercritical fluid chromatography
  • SFC-MS means supercritical fluid chromatography /mass spectrometry
  • LC-MS means liquid chromatography /mass spectrometry
  • HPLC means high-performance liquid chromatography
  • R t means retention time (in minutes)
  • [M+H] + means the protonated mass of the free base of the compound
  • wt means weight
  • DCM means dichloromethane
  • EtOAc means ethyl acetate
  • NMP means N-methylpyrrolidone
  • sat means saturated
  • sltn means
  • RS Whenever the notation “RS” is indicated herein, it denotes that the compound is a racemic mixture at the indicated centre, unless otherwise indicated.
  • the stereochemical configuration for centres in some compounds has been designated R or S when the mixture(s) was separated; for some compounds, the stereochemical configuration at indicated centres has been designated as “i?*” or S* when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically/diastereomerically pure.
  • the enantiomeric excess of compounds reported herein was determined by analysis of the racemic mixture by supercritical fluid chromatography (SFC) followed by SFC comparison of the separated enantiomer(s).
  • Microwave assisted reactions were performed in a single-mode reactor: InitiatorTM Sixty EXP microwave reactor (Biotage AB), or in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc.).
  • TLC Thin layer chromatography
  • silica gel 60 F254 plates Merck
  • Automated flash column chromatography was performed using ready-to-connect cartridges, on irregular silica gel, particle size 15-40 pm (normal phase disposable flash columns) on different flash systems: either a SPOT or LAFLASH systems from Armen Instrument, or PuriFlash®430evo systems from Interchim, or 971-FP systems from Agilent, or Isolera 1SV systems from Biotage.
  • Trifluoroacetic acid (2.14 mL, 27.8 mmol) was added to a solution of intermediate 2c (246 mg, 0.84 mmol) in DCM (7.12 mL) at rt. The mixture was stirred at rt for 90 min.
  • Trifluoroacetic acid (0.81 mL, 10.9 mmol) was added to a solution of intermediate 2d (167 mg, 0.54 mmol) in dry DCM (6 mL) at rt. The mixture was stirred at rt for 2 h. The volatiles were evaporated in vacuo and the residue thus obtained was dissolved in MeOH (8 mL) and was added to a solid phase reactor containing Amberlyst®26 hydroxide form (CAS: 39339-85-0, 849 mg, loading 3.2 mmol/g) at rt and the mixture was shaken for 45 min. The resin was filtered and washed with DCM/MeOH.
  • Trifluoroacetic acid (0.91 mL, 12.2 mmol) was added to a solution of intermediate 3 (200 mg, 0.61 mmol) in dry DCM (8 mL) at rt. The mixture was stirred at rt for 2 h. The volatiles were evaporated in vacuo and the residue thus obtained was dissolved in MeOH (8 mL) and was added to a solid phase reactor containing Amberlyst®26 hydroxide form (CAS: 39339-85-0, 956 mg, loading 3.2 mmol/g) at rt and the mixture was shaken for 45 min. The resin was filtered and washed with DCM/MeOH. The combined filtrates were concentrated in vacuo to yield intermediate le (141 mg, 99%) as a sticky yellow solid.
  • Trifluoroacetic acid (1.7 mL, 22.8 mmol) was added to a solution of intermediate 2f (321 mg, 75% pure) in dry DCM (8 mL) at rt. The mixture was stirred at rt for 2 h. The volatiles were evaporated in vacuo and the residue thus obtained was dissolved in MeOH (8 mL) and was added to a solid phase reactor containing Amberlyst®26 hydroxide form (CAS: 39339-85-0, 1.78 g, loading 3.2 mmol/g) at rt and the mixture was shaken for 45 min. The resin was filtered and washed with DCM/MeOH.
  • Trifluoroacetic acid (1.82 mL, 24.5 mmol) was added to a solution of intermediate 2g (900 mg, 40% pure) in dry DCM (10 mL) at rt. The mixture was stirred at rt for 2 h. The volatiles were evaporated in vacuo and the residue thus obtained was dissolved in MeOH (10 mL) and was added to a solid phase reactor containing Amberlyst®26 hydroxide form (CAS: 39339-85-0, 1.91 g, loading 3.2 mmol/g) at rt and the mixture was shaken for 45 min. The resin was filtered and washed with DCM/MeOH.
  • Intermediate lh-3 was prepared according to an analogous procedure to the one used for the synthesis of intermediate lh-1 using intermediate 2i-l as starting material.
  • Intermediate 2g-2 was prepared according to an analogous procedure to the one used for the synthesis of intermediate 2g-l using isothiazol-3(2//)-one (CAS: 2682-20-4) as starting material.
  • Di-/e/V-butyl azodicarboxylate (CAS: 870-50-8; 343 mg, 1.49 mmol) was added to a stirred solution of 5-hydroxy-2-methylpyridine (CAS: 1121-78-4, 108 mg, 0.99 mmol), (25'.4//)-/c /-butyl 4-hydroxy-2-methylpyrrolidine-l-carboxylate (CAS: 114676-61-8; 200 mg, 0.99 mmol) and triphenylphosphine (391 mg, 1.49 mmol) in toluene (6 mL) at 0 °C under N2.
  • Intermediate 2j-2 was prepared according to an analogous procedure to the one used for the synthesis of intermediate 2j-l using 5-(bromomethyl)-2-methylpyridine (CAS:802559-38-2) as starting material.
  • Intermediate 2j-3 was prepared according to an analogous procedure to the one used for the synthesis of intermediate 2j-l using 5-(bromomethyl)-2-methylpyrimidine (CAS:792187-67-8) as starting material.
  • Acetic anhydride (CAS: 108-24-7; 13.2 g, 129.8 mmol) was added to a stirred mixture of methyl 6-amino-5-bromopyridine-2-carboxylate (CAS: 178876-82-9; 30 g, 129.8 mmol) in toluene (600 mL) under N2. The mixture was stirred at 100 °C for 36 h and then the solvent evaporated in vacuo. The residue was purified by flash column chromatography (S1O2; EtOAc in petroleum ether, gradient from 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield intermediate 4a (14.0 g, 40%) as a white solid.
  • Phosphorus pentasulfide (1.70 g, 7.67 mmol) was added to a suspension of intermediate 4e (1.38 g, 5.90 mmol) in THF (32.2 mL). The mixture was stirred at rt for 16 h and an additional amount of phosphorus pentasulfide (0.39 g, 1.77 mmol) was added. The mixture was stirred at rt for another 16 h and then CS2CO3 (3.08 g, 9.44 mmol) was added. The mixture was stirred at 70 °C for 16 h and then additional quantity of CS2CO3 (3.08 g, 9.44 mmol) was added.
  • the solution was cooled to 0 °C and a mixture of O 3 /O 2 was passed through the flask until the red color dissipated (1 h).
  • the reaction was purged with N2 for 10 min. Then, the reaction was diluted with water and DCM. The organic layer was separated, dried
  • Intermediate 8 was prepared following an analogous procedure to the one described for the synthesis of intermediate 5 using intermediate 7 as starting material. Intermediate 8 was obtained in 95% yield as a yellowish oil.
  • Intermediate 9 was prepared following an analogous procedure to the one described for the synthesis of intermediate 6 using intermediate 8 as starting material. Intermediate 9 was obtained in 97% yield as a brown solid.
  • Trimethylboroxime (CAS: 823-96-1; 0.22 mL, 1.55 mmol) was added dropwise to a stirred mixture of intermediate 2d-6 (405 mg, 1.29 mmol), K3PO4 (545 mg, 2.58 mmol), X-Phos (CAS: 564483-18-7; 61 mg, 0.13 mmol) and Pd2(dba)3 (CAS: 51364- 51-3; 59 mg, 0.064 mmol) in dry 1,4-dioxane (6 mL) under nitrogen at rt. The mixture was stirred at 95 °C for 16 h. Water and EtOAc were added.
  • Trifluoro acetic acid (0.36 mL, 4.84 mmol) was added to a stirred solution of intermediate 20 (103 mg, 0.24 mmol) in DCM (5 mL) at 0 °C. The mixture was stirred at rt for 2 h. Volatiles were evaporated under vacuo. The crude product was dissolved in MeOH (5 mL) and was added to a solid phase reactor containing Amberlyst®26 hydroxide form (CAS: 39339-85-0; loading 3.2 mmol/g, 378 mg,) at rt and the mixture was shaken for 45 min. The resin was filtered and washed with DCM/MeOH. The combined filtrates were concentrated in vacuo to yield intermediate 21 (79 mg, 81%) as a brown sticky solid.
  • Trifluoroacetic anhydride (CAS: 407-25-0; 0.268 mL, 1.88 mmol) was added to a stirred solution of intermediate 26 (427 mg, 1.25 mmol) and triethylamine (0.528 mL, 3.76 mmol) in anhydrous DCM (10 mL) at 0 °C. The mixture was stirred at rt for 16 h diluted with NaHC0 3 aq. sat. sltn. and extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 29/71). The desired fractions were collected and concentrated in vacuo to yield intermediate 28 as a yellow sticky solid. PREPARATION OF INTERMEDIATE 29
  • Trimethylboroxime (CAS: 823-96-1; 0.11 mL, 0.78 mmol) was added to a stirred solution of intermediate 43 (110 mg, 0.31 mmol), K3PO4 (133 mg, 0.63 mmol) and X- Phos (CAS564483-18-7; 15 mg, 0.031 mmol) in anhydrous 1,4-dioxane (5 mL) under N2.
  • the reaction mixture was stirred at 95 °C for 16 h.
  • the reaction mixture was dilutedwith water and extracted with EtOAc. The organic layer was separated, dried (MgS0 4 ), filtered and the solvents evaporated in vacuo.
  • Titanium(IV) isopropoxide (CAS: 546-68-9; 0.213 mL, 0.73 mmol) was added to a stirred solution of intermediate la (0.1 g, 0.48 mmol) and intermediate 4d (96 mg, 0.53 mmol) in DCM (3.1 mL) at rt. The mixture was stirred at rt for 7 h. Then sodium triacetoxyborohydride (308 mg, 1.45 mmol) was added and the mixture was stirred 16 h at rt. Then NaHC0 3 aq. sat. soltn. Was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvents removed in vacuo.
  • Titanium(IV) isopropoxide (CAS: 546-68-9; 0.255 mL, 0.87 mmol) was added to a stirred solution of intermediate la (0.12 g, 0.58 mmol) and 2,3-dihydro-[l,4]- dioxino[2,3-Z>]pyridine-6-carbaldehyde (CAS: 615568-24-6; 106 mg, 0.65 mmol) in DCM (3.7 mL) at rt. The mixture was stirred at rt for 7 h. Then sodium triacetoxyborohydride (370 mg, 1.74 mmol) was added and the mixture was stirred 16 h at rt. Then NaHCC aq. sat. soltn.
  • Titanium(IV) isopropoxide (CAS: 546-68-9; 0.213 mL, 0.73 mmol) was added to a stirred solution of intermediate lb (0.10 g, 0.48 mmol) and 2,3-dihydro-[l,4]- dioxino[2,3-b]pyridine-6-carbaldehyde (CAS: 615568-24-6; 88 mg, 0.53 mmol) in DCM (3.1 mL) at rt. The mixture was stirred at rt for 16 h. Then sodium triacetoxyborohydride (308 mg, 1.45 mmol) was added and the mixture was stirred 3 h at rt. Then NaHC0 3 aq. sat.
  • Titanium(IV) isopropoxide (CAS: 546-68-9; 0.345 mL, 1.18 mmol) was added to a stirred solution of intermediate la (0.16 g, 0.79 mmol) and intermediate 4j (185 mg, 0.94 mmol) in DCM (5 mL) at rt. The mixture was stirred at rt for 16 h. Then sodium triacetoxyborohydride (0.5 g, 2.36 mmol) was added and the mixture was stirred 3 h at rt. Then NFECl aq. sat. soltn. Was added and the mixture was filtered through and celite® pad. The filtrate was extracted with DCM.
  • Titanium(IV) isopropoxide (CAS: 546-68-9; 0.255 mL, 0.87 mmol) was added to a stirred solution of intermediate la (0.12 g, 0.58 mmol) and intermediate 4p (95 mg,
  • Di-/er/-butyl azodicarboxylate (CAS: 870-50-8; 119 mg, 0.52 mmol) was added to a stirred solution of 2-methylpyrimidin-5-ol (CAS: 35231-56-2, 44 mg, 0.40 mmol), intermediate 1-19 (100 mg, 0.40 mmol) and triphenylphosphine (136 mg, 0.52 mmol) in toluene (1.3 mL) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h.
  • Compounds 73a and 73b were taken up in DCM and then a 4 N HC1 solution in 1,4-dioxane was added to yield compound 73a (HC1 salt, 10 mg, 11%) and 73b (HC1 salt, 14 mg, 16%) as white solids.
  • ANALYTICAL PART MELTING POINTS Values are peak values and are obtained with experimental uncertainties that are commonly associated with this analytical method.
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • the SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, an UV detector equipped with a high-pressure flow cell standing up to 400 bars. Data acquisition was performed with appropriate software.
  • SFC Analytical Supercritical fluid chromatography
  • Analytical SFC-MS Methods (Flow expressed in mL/min; column temperature (T) in °C; run time in minutes; backpressure (BPR) in bars. TABLE 6.
  • Analytical SFC data - R t means retention time (in minutes), [M+H] + means the protonated mass of the compound, method refers to the method used for (SFC)MS analysis of enantiomerically pure compounds.
  • the assay is based on the inhibition of the hydrolysis of fluorescein mono-B-D-N- Acetyl-Glucosamine (FM-GlcNAc) (Mariappa et al. 2015, Biochem J 470:255) by the recombinant human Meningioma Expressed Antigen 5 (MGEA5), also referred to as O-GlcNAcase (OGA).
  • MGEA5 Meningioma Expressed Antigen 5
  • O-GlcNAcase O-GlcNAcase
  • the hydrolysis FM-GlcNAc Marker Gene technologies, cat # M1485) results in the formation of B-D-N-glucosamineacetate and fluorescein.
  • the fluorescence of the latter can be measured at excitation wavelength 485 nm and emission wavelength 538nm. An increase in enzyme activity results in an increase in fluorescence signal.
  • Full length OGA enzyme was purchased at OriGene (cat # TP322411). The enzyme was stored in 25 mM Tris.HCl, pH 7.3, 100 mM glycine, 10% glycerol at -20 °C. Thiamet G and GlcNAcStatin were tested as reference compounds (Yuzwa et al. 2008 Nature Chemical Biology 4:483; Yuzwa et al. 2012 Nature Chemical Biology 8:393). The assay was performed in 200mM Citrate/phosphate buffer supplemented with 0.005% Tween-20. 35.6 gNa 2 HP0 4 2 3 ⁇ 40 (Sigma, # C0759) were dissolved in 1 L water to obtain a 200 mM solution.
  • citric acid (Merck, # 1.06580) was dissolved in 1 L water to obtain a 100 mM solution. pH of the sodiumphosphate solution was adjusted with the citric acid solution to 7.2.
  • the buffer to stop the reaction consists of a 500 mM Carbonate buffer, pH 11.0. 734 mg
  • FM-GlcNAc were dissolved in 5.48 mL DMSO to obtain a 250 mM solution and was stored at -20 °C. OGA was used at a 2nM concentration and FM-GlcNAc at a lOOuM final concentration. Dilutions were prepared in assay buffer.
  • HEK293 cells inducible for P301L mutant human Tau were established at Janssen.
  • Thiamet-G was used for both plate validation (high control) and as reference compound (reference EC50 assay validation).
  • OGA inhibition is evaluated through the immunocytochemical (ICC) detection of O-GlcNAcylated proteins by the use of a monoclonal antibody (CTD110.6; Cell Signaling, #9875) detecting O- GlcNAcylated residues as previously described (Dorfmueller et al. 2010 Chemistry & biology, 17:1250). Inhibition of OGA will result in an increase of O- GlcNAcylated protein levels resulting in an increased signal in the experiment.
  • ICC pictures are imaged with a Perkin Elmer Opera Phenix plate microscope and quantified with the provided software Perkin Elmer Harmony 4.1.
  • Cells were propagated in DMEM high Glucose (Sigma, #D5796) following standard procedures. 2 days before the cell assay cells are split, counted and seeded in Poly-D- Lysine (PDL) coated 96-wells (Greiner, #655946) plate at a cell density of 12,000 cells per cm 2 (4,000 cells per well) in IOOmI of Assay Medium (Low Glucose medium is used to reduce basal levels of GlcNAcylation) (Park et al. 2014 The Journal of biological chemistry 289:13519). At the day of compound test medium from assay plates was removed and replenished with 90pl of fresh Assay Medium.
  • PDL Poly-D- Lysine
  • Imaging is performed using Perkin Elmer Phenix Opera using a water 20x objective and recording 9 fields per well. Intensity readout at 488nm is used as a measure of O-GlcNAcylation level of total proteins in wells. To assess potential toxicity of compounds nuclei were counted using the Hoechst staining. I C50- values are calculated using parametric non-linear regression model fitting. As a maximum inhibition Thiamet G at a 200uM concentration is present on each plate. In addition, a concentration response of Thiamet G is calculated on each plate.
  • Microsomal Stability Assay Human or mouse microsomes were incubated with the test compound at 37°C in the presence of the co-factor, NADPH. The reaction was terminated by the addition of methanol containing internal standard. Following centrifugation, the supernatant was analysed by LC-MS/MS. Depletion of test compound in the presence of liver microsomes was monitored over a 45 minute time period. The In peak area ratio (compound peak area/intemal standard peak area) was plotted against time and the gradient determined. The following values could then be calculated:

Abstract

La présente invention concerne des inhibiteurs de O-GlcNAc hydrolase (OGA). L'invention concerne également des compositions pharmaceutiques comprenant de tels composés, des procédés de préparation de tels composés et compositions, et l'utilisation de tels composés et compositions pour la prévention et le traitement de troubles dans lesquels l'inhibition de l'OGA est bénéfique, telles que les tauopathies, en particulier la maladie d'Alzheimer ou la paralysie supranucléaire progressive ; et les maladies neurodégénératives accompagnées d'une pathologie tau, en particulier la sclérose latérale amyotrophique ou la démence du lobe fronto-temporale provoquée par des mutations C90RF72 ; ou des alpha synucléinopathies, en particulier la maladie de Parkinson, la démence causée par la maladie de Parkinson (ou un trouble neurocognitif causé par la maladie de Parkinson), la démence à corps de Lewy, l'atrophie multisystémique ou l'alpha synucléinopathie causée par la maladie de Gaucher.
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Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012117219A1 (fr) 2011-03-02 2012-09-07 Summit Corporation Plc Dérivés de pyrrolidine en tant qu'inhibiteurs sélectifs de glycosidase et leurs utilisations
WO2014159234A1 (fr) 2013-03-14 2014-10-02 Merck Patent Gmbh Inhibiteurs de glycosidases
WO2016030443A1 (fr) 2014-08-28 2016-03-03 Asceneuron Sa Inhibiteurs de glycosidases
WO2017106254A1 (fr) 2015-12-18 2017-06-22 Merck Sharp & Dohme Corp. Inhibiteurs de glycosidase et leurs utilisations
WO2017114639A1 (fr) 2015-12-29 2017-07-06 fos4X GmbH Procédé permettant de pronostiquer une accumulation de givre sur une pale de rotor d'une éolienne et utilisation dudit procédé
WO2017144637A1 (fr) 2016-02-25 2017-08-31 Asceneuron S. A. Sels d'addition d'acide de dérivés de pipérazine
WO2017144633A1 (fr) 2016-02-25 2017-08-31 Asceneuron S. A. Inhibiteurs de glycosidases
WO2018109202A1 (fr) 2016-12-16 2018-06-21 Janssen Pharmaceutica Nv Composés inhibiteurs d'oga monocyclique
WO2018140299A1 (fr) 2017-01-27 2018-08-02 Eli Lilly And Company N-[4-fluoro-5-[[(2s,4s)-2-méthyl-4-[(5-méthyl-1,2,4-oxadiazol-3-yl)méthoxy]-1-pipéridyl]méthyl]thiazol-2-yl]acétamide utilisés en tant qu'inhibiteur d'oga
WO2018154133A1 (fr) 2017-02-27 2018-08-30 Janssen Pharmaceutica Nv Dérivés de [1,2,4]-triazolo [1,5-a]-pyrimidinyle substitués par de la pipéridine, de la morpholine ou de la pipérazine utilisés en tant qu'inhibiteurs d'oga
WO2018217558A1 (fr) 2017-05-25 2018-11-29 Eli Lilly And Company Composés de 5-méthyl-1,3,4-oxadiazol-2-yl
WO2019178191A1 (fr) 2018-03-14 2019-09-19 Biogen Ma Inc. Inhibiteurs d'o-glycoprotéine-2-acétamido-2-désoxy-3-d-glycopyranosidase
WO2019243527A1 (fr) * 2018-06-20 2019-12-26 Janssen Pharmaceutica Nv Composés inhibiteurs d'oga
WO2019243528A1 (fr) * 2018-06-20 2019-12-26 Janssen Pharmaceutica Nv Composés inhibiteurs d'oga

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012117219A1 (fr) 2011-03-02 2012-09-07 Summit Corporation Plc Dérivés de pyrrolidine en tant qu'inhibiteurs sélectifs de glycosidase et leurs utilisations
WO2014159234A1 (fr) 2013-03-14 2014-10-02 Merck Patent Gmbh Inhibiteurs de glycosidases
WO2016030443A1 (fr) 2014-08-28 2016-03-03 Asceneuron Sa Inhibiteurs de glycosidases
WO2017106254A1 (fr) 2015-12-18 2017-06-22 Merck Sharp & Dohme Corp. Inhibiteurs de glycosidase et leurs utilisations
WO2017114639A1 (fr) 2015-12-29 2017-07-06 fos4X GmbH Procédé permettant de pronostiquer une accumulation de givre sur une pale de rotor d'une éolienne et utilisation dudit procédé
WO2017144637A1 (fr) 2016-02-25 2017-08-31 Asceneuron S. A. Sels d'addition d'acide de dérivés de pipérazine
WO2017144633A1 (fr) 2016-02-25 2017-08-31 Asceneuron S. A. Inhibiteurs de glycosidases
WO2018109202A1 (fr) 2016-12-16 2018-06-21 Janssen Pharmaceutica Nv Composés inhibiteurs d'oga monocyclique
WO2018140299A1 (fr) 2017-01-27 2018-08-02 Eli Lilly And Company N-[4-fluoro-5-[[(2s,4s)-2-méthyl-4-[(5-méthyl-1,2,4-oxadiazol-3-yl)méthoxy]-1-pipéridyl]méthyl]thiazol-2-yl]acétamide utilisés en tant qu'inhibiteur d'oga
WO2018154133A1 (fr) 2017-02-27 2018-08-30 Janssen Pharmaceutica Nv Dérivés de [1,2,4]-triazolo [1,5-a]-pyrimidinyle substitués par de la pipéridine, de la morpholine ou de la pipérazine utilisés en tant qu'inhibiteurs d'oga
WO2018217558A1 (fr) 2017-05-25 2018-11-29 Eli Lilly And Company Composés de 5-méthyl-1,3,4-oxadiazol-2-yl
WO2019178191A1 (fr) 2018-03-14 2019-09-19 Biogen Ma Inc. Inhibiteurs d'o-glycoprotéine-2-acétamido-2-désoxy-3-d-glycopyranosidase
WO2019243527A1 (fr) * 2018-06-20 2019-12-26 Janssen Pharmaceutica Nv Composés inhibiteurs d'oga
WO2019243528A1 (fr) * 2018-06-20 2019-12-26 Janssen Pharmaceutica Nv Composés inhibiteurs d'oga

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
ALZHEIMER'S & DEMENTIA, vol. 12, 2016, pages 292 - 323
DORFMUELLER ET AL., CHEMISTRY & BIOLOGY, vol. 17, 2010, pages 1250
DUBOIS B ET AL., LANCET NEUROL, vol. 13, 2014, pages 614 - 629
LEVINE, PM ET AL., PNAS, vol. 116, no. 5, 29 January 2019 (2019-01-29), pages 1511 - 1519
LEWIS, YE ET AL., ACS CHEM BIOL, vol. 2, no. 4, 21 April 2017 (2017-04-21), pages 1020 - 1027
MARIAPPA ET AL., BIOCHEM J, vol. 470, 2015, pages 255
MAROTTA, NP ET AL., NAT CHEM, vol. 11, November 2015 (2015-11-01), pages 913 - 20
PARK ET AL., THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 289, 2014, pages 13519
RADICE ET AL.: "Mutagenicity evaluation of 2-amino-4-thiazole acetic acid", PHARMA WORLD, 2014
SPERLING, RA ET AL., ALZHEIMERS DEMENT, vol. 7, 2011, pages 280 - 292
YUZWA ET AL., NATURE CHEMICAL BIOLOGY, vol. 4, 2008, pages 483
YUZWA ET AL., NATURE CHEMICAL BIOLOGY, vol. 8, 2012, pages 393

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