WO2018153508A2 - Inhibiteurs de la sulfoximine glycosidase - Google Patents

Inhibiteurs de la sulfoximine glycosidase Download PDF

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Publication number
WO2018153508A2
WO2018153508A2 PCT/EP2017/071385 EP2017071385W WO2018153508A2 WO 2018153508 A2 WO2018153508 A2 WO 2018153508A2 EP 2017071385 W EP2017071385 W EP 2017071385W WO 2018153508 A2 WO2018153508 A2 WO 2018153508A2
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WO
WIPO (PCT)
Prior art keywords
mmol
formula
compound
diastereomers
compounds
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PCT/EP2017/071385
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English (en)
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WO2018153508A3 (fr
Inventor
Anna Quattropani
Santosh S. Kulkarni
Awadut Gajendra Giri
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Asceneuron S.A.
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Publication date
Priority claimed from PCT/EP2017/054268 external-priority patent/WO2017144633A1/fr
Priority claimed from PCT/EP2017/054280 external-priority patent/WO2017144639A1/fr
Priority to BR112019017514-8A priority Critical patent/BR112019017514A2/pt
Priority to PCT/EP2017/071385 priority patent/WO2018153508A2/fr
Priority to KR1020197027278A priority patent/KR20190118184A/ko
Priority to MX2019010085A priority patent/MX2019010085A/es
Priority to SG11201907774VA priority patent/SG11201907774VA/en
Priority to EA201991697A priority patent/EA201991697A1/ru
Priority to KR1020237005097A priority patent/KR102620279B1/ko
Priority to CA3053200A priority patent/CA3053200C/fr
Application filed by Asceneuron S.A. filed Critical Asceneuron S.A.
Priority to AU2017400271A priority patent/AU2017400271B2/en
Priority to CN201780089984.7A priority patent/CN110770226B/zh
Priority to JP2019545961A priority patent/JP7082446B2/ja
Priority to EP17758140.2A priority patent/EP3585783A2/fr
Priority to US16/488,139 priority patent/US11261183B2/en
Publication of WO2018153508A2 publication Critical patent/WO2018153508A2/fr
Publication of WO2018153508A3 publication Critical patent/WO2018153508A3/fr
Priority to IL268501A priority patent/IL268501A/en
Priority to ZA2019/05405A priority patent/ZA201905405B/en
Priority to US17/552,100 priority patent/US20220177470A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a medicament comprising a compound of formula (I)
  • A, R, W, Q, n and m have the meaning according to the claims, and/or physiologically acceptable salts, tautomers, solvates, stereoisomers and derivatives thereof.
  • the compounds of formula (I) can be used as glycosidase inhibitors.
  • Objects of the invention are also pharmaceutical compositions comprising the compounds of formula (I), and the use of the compounds of formula (I) for the treatment of one or more tauopathies and Alzheimer's disease.
  • a wide range of cellular proteins, both nuclear and cytoplasmic, are post-translationally modified by the addition of the monosaccharide 2-acetamido-2-deoxy- -D-glucopyranoside ( ⁇ - ⁇ -acetyl glucosamine) which is attached via an O-glycosidic linkage.
  • This modification is generally referred to as O-linked N-acetylglucosamine or O-GlcNAc.
  • the enzyme responsible for post-translationally linking ⁇ - ⁇ -acetylglucosamine (GlcNAc) to specific serine and threonine residues of numerous nucleocytoplasmic proteins is O-GlcNAc transferase (OGTase).
  • a second enzyme, known as O- GlcNAcase removes this post-translational modification to liberate proteins making the O-GlcNAc- modification a dynamic cycle occurring several times during the lifetime of a protein.
  • O-GlcNAc-modified proteins regulate a wide range of vital cellular functions including, for example, transcription, proteasomal degradation and cellular signaling.
  • O-GlcNAc is also found on many structural proteins. For example, it has been found on a number of cytoskeletal proteins, including neurofilament proteins, synapsins, synapsin-specific clathrin assembly protein AP-3 and Ankyrin-G.
  • O-GlcNAc modification has been found to be abundant in the brain. It has also been found on proteins clearly implicated in the etiology of several diseases including tauopathies, Alzheimer's disease (AD), synucleinopathies, Parkinson's disease, amyotrophic lateral sclerosis, and cancer.
  • AD Alzheimer's disease
  • PPP progressive supranuclear palsy
  • CBD corticobasal degeneration
  • APD argyrophilic grain disease
  • GTT globular glial tauopathy
  • FTLD-17 frontotemporal dementia and parkinsonism linked to chromosome-17
  • NFTs neurofibrillary tangles
  • NFTs are also a histopathological hallmark of chronic traumatic encephalopathy that is a consequence of traumatic brain injury.
  • NFTs are aggregates of paired helical filaments (PHFs) and are composed of an abnormal form of the cytoskeletal protein "tau".
  • tau stabilizes a key cellular network of microtubules that is essential for distributing proteins and nutrients within neurons.
  • tau becomes hyperphosphorylated, disrupting its normal function, forming PHFs and ultimately aggregating to form NFTs.
  • Six isoforms of tau are found in the human brain.
  • AD patients all six isoforms of tau are found in NFTs, and all are markedly hyperphosphorylated.
  • Tau in healthy brain tissue bears only 2 or 3 phosphate groups, whereas those found in the brains of AD patients bear, on average, 8 phosphate groups.
  • O-GlcNAc This reciprocal relationship between O-GlcNAc and phosphorylation has been termed the "Yin-Yang hypothesis" and has gained strong biochemical support by the recent discovery that the enzyme OGTase forms a functional complex with phosphatases that act to remove phosphate groups from proteins. Like phosphorylation, O-GlcNAc is a dynamic modification that can be removed and reinstalled several times during the lifespan of a protein. Suggestively, the gene encoding O-GlcNAcase has been mapped to a chromosomal locus that is linked to AD. Hyperphosphorylated tau in human AD brains has markedly lower levels of O-GlcNAc than are found in healthy human brains.
  • O-GlcNAc transferase O-GlcNAc transferase
  • TDP-43 aggregating proteins that are associated with amyotrophic lateraly sclerosis
  • SOD-I superoxide-dismutase I
  • TDP-43 frontotemporal lobar degeneration
  • neurodegenerative diseases including Parkinson's disease and related synucleinopathies, and Huntington's disease.
  • O-GlcNAcase O-glycoprotein-2-acetamido- 2-deoxy- -D-glucopyranosidase
  • O-GlcNAcase Consistent with the presence of O-GlcNAc on many intracellular proteins, the enzyme O-GlcNAcase appears to have a role in the etiology of several diseases including type II diabetes, AD and cancer. Although O-GlcNAcase was likely isolated earlier on, about 20 years elapsed before its biochemical role in acting to cleave O-GlcNAc from serine and threonine residues of proteins was understood. More recently O-GlcNAcase has been cloned, partially characterized, and suggested to have additional activity as a histone acetyltransferase.
  • O-GlcNAcase a major challenge in developing inhibitors for blocking the function of mammalian glycosidases, including O-GlcNAcase, is the large number of functionally related enzymes present in tissues of higher eukaryotes. Accordingly, the use of non-selective inhibitors in studying the cellular and organismal physiological role of one particular enzyme is complicated because complex phenotypes arise from the concomitant inhibition of such functionally related enzymes. In the case of ⁇ - ⁇ -acetylglucosaminidases, existing compounds that act to block O-GlcNAcase function are non-specific and act potently to inhibit the lysosomal ⁇ -hexosaminidases. Low molecular weight OGA inhibitors are e.g.
  • the present invention has the objective of providing novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
  • plasma protein binding is an important differentiating factor in drug
  • Plasma protein binding information can be used to estimate the unbound and thus effective concentration of drugs in order to establish pharmacokinetic/pharmacodynamic (PKPD) relationships in animals and humans.
  • PKPD pharmacokinetic/pharmacodynamic
  • the introduction of a sulfoximine group results in an increased unbound fraction (decreased PPB) for compounds of Formula (I).
  • the preferred compounds of the invention provide a low variability of fractions unbound across several animal species including humans.
  • free drug concentrations in tissues are increased, directly yielding higher unbound brain concentrations (as measured by cerebrospinal fluid concentrations as surrogate) with similar effects measurable across different species which often greatly improve predictability of human PK and result in lower effective human dose due to the same extent of increase of unbound fractions across species (Liu et al. J. Med. Chem. 2014, 57, 8238).
  • the compounds according to the invention and salts thereof have very valuable pharmacological properties.
  • they act as glycosidase inhibitors, that provide increased unbound, i.e. free fractions in plasma.
  • the compounds according to the invention and salts thereof consistently provide increased free fractions in plasma across species including humans (low inter-species variability), which make them ideal for pharmaceutical development and their application as a drug.
  • very preferred compounds of the present invention exhibit favorable microsome stability data a measure according to the examples.
  • the invention relates to compounds of formula (I)
  • R is straight chain or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH; W is CH or N;
  • N or CR "' is O, S, SO or S0 2
  • R “ , R” denote each independently H, Hal or straight chain or branched alkyl having 1 to 12 carbon atoms; R , R independently denote H, Hal, NR 3 R 4 , CHR 3 R 4 , OR 3 , CN or a straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from O, NR 3 , S, SO, S0 2 , S(0)(NR 3' ), N(SO)R 3' , CO, COO, OCO, CONR 3 , NR 3 CO,
  • R independently denote one of the following groups:
  • Z 2 , Z 3 independently denote CR 5 or N; is N, CH, CON, COCH;
  • Z 6 is CH 2 , CO, S(0)(NR 3 ), N(SO)R 3 , ;
  • Z 7 is C(R 3' ) 2 , S, O, NR 3' ; s denotes 0 or 1 ;
  • T is N. CH or CR 7 ;
  • R 3 denotes H or a straight chain or branched alkyl group having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from S0 2 , CO, O and wherein 1 to 5 hydrogen atoms may be replaced by Hal;
  • R 5 , R 6 , R 7 independently denote H, Hal, NR 3 R 4 , N0 2 or a straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from O, NR 3 , S, SO, S0 2 , S(0)(NR 3' ), N(SO)R 3' , CO, COO, OCO, CONR 3 , 3CO
  • R 5 , R 6 , R 7 denote Ar, Het or Cyc or one of the following groups:
  • H denotes H or straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from SO, S0 2 , S(0)(NR 3 ), N(SO)R 3' , CO, COO, OCO, CONR 3 , NR 3 CO, and
  • 1 to 5 hydrogen atoms may be replaced by CN, OR 3 , SR 3 , Hal, NR 3 R 4 N0 2 or b one of the followin groups:
  • R denote one of the following groups:
  • Hal denotes F, CI, Br or I
  • Het denotes a saturated, unsaturated or aromatic ring, being monocyclic or bicyclic or fused-bicyclic and having 3- to 8- members and containing 1 to 4 heteroatoms selected from N, O and S, which may be substituted by 1 to 3 substituents selected from R 5 , Hal and OR 3 ;
  • Ar denotes a 6-membered carbocyclic aromatic ring or a fused or non-fused bicylic
  • aromatic ring system which is optionally substituted by 1 to 3 substituents
  • Cyc denotes a saturated or an unsaturated carbocyclic ring having from 3 to 8 carbon atoms which is optionally substituted by 1 to 3 substituents independently selected from R 5 or Hal or OH; m and n denote independently from one another 0, 1 , 2 or 3, t and q denote independently from one another 0, 1 , 2 or 3, with t + q ⁇ 1
  • Z 5 and Z 6 is the group S(0)(NR 3' ) or N(SO)R 3' or
  • R '" , R "" , R 5 , R 6 , R 7 and R 8 is or contains a sulfoximine group selected from:
  • formula (I) includes the following two enantiomers of formula la and lb:
  • the invention also relates to a mixture of, i.e. a composition comprising, compounds la and lb as set out above, having identical groups A, R, W, Q, n and m, in equal or unequal amounts.
  • R in formula I, la and lb is preferably methyl.
  • the indices m and n in formula I, la and lb are preferably simultaneously 1.
  • compounds of formula I are the compounds of formula A and B:
  • Preferred compounds of the present invention are preferably a single isomer, in their non-racemic form, i.e. as diasteromerically and enatiomerically pure compounds or their diastereomerically and enaniomerically enriched mixtures of the respective diastereomers and enantiomers.
  • R is an unsubstituted straight chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n- propyl or iso-butyl, the S-configuration at the stereogenic center bearing the group R is preferred. Very preferred are formulae lb and B.
  • a further preferred compound of formula I is a single enantiopure or enantiomerically enriched diastereoisomer, i.e. a compound wherein the stereogenic center bearing the group R has an S- configuration and any other stereogenic center within the compound has either an S- or an R- configu ration.
  • compounds of formula I are preferred that contain one ore more preferred groups such as R' and indices such as m or n.
  • Compounds of formula I are the more preferred, the more preferred groups or indices they contain.
  • the connecting atom in the respective group is preferably a carbon atom or the respective group is H.
  • the invention also relates to the use of compounds of formula (I) as a medicament.
  • the compound is defined to include pharmaceutically usable derivatives, solvates, prodrugs, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios.
  • pharmaceutically usable derivatives is taken to mean, for example, the salts of the compounds according to the invention and also so-called prodrug compounds.
  • solvates of the compounds is taken to mean adductions of inert solvent molecules onto the compounds, which are formed owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alkoxides.
  • the invention also comprises solvates of salts of the compounds according to the invention.
  • prodrug is taken to mean compounds according to the invention which have been modified by means of, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to form the effective compounds according to the invention.
  • biodegradable polymer derivatives of the compounds according to the invention include biodegradable polymer derivatives of the compounds according to the invention.
  • the compounds of the invention can be in the form of any desired prodrugs such as, for example, esters, carbonates, carbamates, ureas, amides or phosphates, in which cases the actually biologically active form is released only through metabolism.
  • Any compound that can be converted in-vivo to provide the bioactive agent i.e. compounds of the invention
  • Various forms of prodrugs are well known in the art.
  • chemical substances are converted in the body into metabolites which may where appropriate likewise elicit the desired biological effect - in some circumstances even in more pronounced form.
  • Any biologically active compound that was converted in-vivo by metabolism from any of the compounds of the invention is a metabolite within the scope and spirit of the invention.
  • the compounds of the invention may be present in the form of their double bond isomers as pure E or Z isomers, or in the form of mixtures of these double bond isomers. Where possible, the compounds of the invention may be in the form of the tautomers, such as keto-enol tautomers. All stereoisomers of the compounds of the invention are contemplated, either in a mixture or in pure or substantially pure form.
  • the compounds of the invention can have asymmetric centers at any of the carbon atoms. Consequently, they can exist in the form of their racemates, in the form of the pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers.
  • the mixtures may have any desired mixing ratio of the stereoisomers.
  • the compounds of the invention which have one or more centers of chirality and which occur as racemates or as diastereomer mixtures can be fractionated by methods known per se into their optical pure isomers, i.e. enantiomers or diastereomers.
  • the separation of the compounds of the invention can take place by column separation on chiral or non-chiral phases or by re- crystallization from an optionally optically active solvent or with use of an optically active acid or base or by derivatization with an optically active reagent such as, for example, an optically active alcohol, and subsequent elimination of the radical.
  • the invention also relates to the use of mixtures of the compounds according to the invention, for example mixtures of two diastereomers, for example in the ratio 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 1 :100 or 1 :1000.
  • mixtures of the compounds according to the invention for example mixtures of two diastereomers, for example in the ratio 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 1 :100 or 1 :1000.
  • These are particularly preferably mixtures of stereoisomeric compounds.
  • An enantiomerically enriched mixture denotes a compound of Formula (I) or related formula having an enantiomeric excess, as measured by methods well known by one skilled in the art, of 10% or more, preferably 50% or more, and more preferably more than 95%. Most preferably an enantiomerically enriched mixture denotes a compound of Formula (I) or related Formulae having an enantiomeric excess of more than 98%.
  • substituents means that the corresponding radical, group or moiety has one or more substituents.
  • a radical has a plurality of substituents, and a selection of various substituents is specified, the substituents are selected independently of one another and do not need to be identical. Even though a radical has a plurality of a specific-designated substituent the expression of such substituent may differ from each other (e.g. methyl and ethyl). It shall be understood accordingly that a multiple substitution by any radical of the invention may involve identical or different radicals. Hence, if individual radicals occur several times within a compound, the radicals can adopt any of the meanings indicated, independently of one another.
  • alkyi or “alkyi group” refers to acyclic saturated or unsaturated hydrocarbon radicals, which may be branched or straight-chain and preferably have 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, i.e. Ci-Ci 0 -alkanyls.
  • suitable alkyi radicals are methyl, ethyl,
  • n-propyl isopropyl, 1 ,1-, 1 ,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2- methylpropyl, 1 , 1 ,2- or 1 ,2,2-trimethylpropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-, 2- or 3- methylbutyl, 1 ,1-, 1 ,2-, 1 ,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,
  • n-pentyl iso-pentyl, neo-pentyl, tert-pentyl, 1-, 2-, 3- or -methyl-pentyl, n-hexyl, 2-hexyl, isohexyl, n- heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n- icosanyl, n-docosanyl.
  • 1 or more, preferable 1 to 3 CH 2 groups may be replaced by other divalent groups accoding to the defintions given above and below.
  • an H atom of alkyi may be replaced by Cyc.
  • alkyi denotes unbranched or branched alkyi having 1-10 C atoms, in which 1-7 H atoms may be replaced independently from one another by Hal.
  • a preferred embodiment of alkyi denotes unbranched or branched alkyi having 1-6 C atoms, in which 1-4 atoms may be replaced independently from one another by Hal.
  • alkyi denotes unbranched or branched alkyi having 1-4 C atoms, in which 1-3 H atoms can be replaced independently from one another by Hal, particularly by F and/or CI. It is most preferred that alkly denotes unbranched or branched alkyi having 1-6 C atoms.
  • Ci-4-alkyl is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 ,1 , 1- trifluoroethyl or bromomethyl, especially methyl, ethyl, propyl or trifluoromethyl. It shall be understood that the respective denotation of alkyi is independently of one another in any radical of the invention.
  • cycloalkyi or “Cyc” for the purposes of this invention refers to saturated and partially unsaturated non-aromatic cyclic hydrocarbon groups/radicals, having 1 to 3 rings, that contain 3 to 20, preferably 3 to 12, more preferably 3 to 9 carbon atoms.
  • the cycloalkyi radical may also be part of a bi- or polycyclic system, where, for example, the cycloalkyi radical is fused to an aryl, heteroaryl or heterocyclyl radical as defined herein by any possible and desired ring member(s).
  • the bonding to the compounds of the general formula (I) can be effected via any possible ring member of the cycloalkyl radical.
  • Suitable cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl and cyclooctadienyl.
  • Cyc denotes cycloalkyl having 3-7 C atoms, in which 1-4 H atoms may be replaced independently of one another by Hal.
  • Preferred is C 3 -C 7 -cycloalkyl. More preferred is C 4 -C 7 -cycloalkyl.
  • C 5 -C 7 -cycloalkyl i.e. cyclopentyl, cyclohexyl or cycloheptyl, highly preferably cyclohexyl. It shall be understood that the respective denotation of Cyc is independently of one another in any radical of the invention.
  • Ar refers to a mono- or polycyclic aromatic hydrocarbon systems having 3 to 14, preferably 3-12, more preferably 4 to 12, most preferably 5 to 10, highly preferably 6 to 8 carbon atoms, which can be optionally substituted.
  • the term “Ar” or “aryl” also includes systems in which the aromatic cycle is part of a bi- or polycyclic saturated, partially unsaturated and/or aromatic system, such as where the aromatic cycle is fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl group as defined herein via any desired and possible ring member of the aryl radical.
  • the bonding to the compounds of the general formula (I) can be effected via any possible ring member of the aryl radical.
  • aryl radicals are phenyl, biphenyl, naphthyl, 1-naphthyl, 2-naphthyl and anthracenyl, but likewise indanyl, indenyl or 1 ,2,3,4-tetrahydronaphthyl.
  • Preferred carboaryls of the invention are optionally substituted phenyl, naphthyl and biphenyl, more preferably optionally substituted monocylic carboaryl having 6- 8 C atoms, most preferably optionally substituted phenyl.
  • Ar and aryl are preferably selected from the following group: phenyl, o-, m- or p-tolyl, o-, m- or p- ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert.-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluoro- phenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-sulfonamidophenyl, o-, m- or p
  • Het denotes preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3- pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1 ,2,3-triazoM-, -4- or -5-yl, 1 ,2,4-triazo-, -3- or 5-yl, 1- or 5-tetrazolyl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,3,4- thiadiazol-2- or -5-yl, 1 ,2,4-thiadiazol
  • the heterocyclic radicals may also be partially or fully hydrogenated.
  • Het can thus also denote, preferably, 2,3-dihydro-2-, -3-, -4- or -
  • Het preferably denotes piperidinyl, 4-hydroxypiperidinyl, piperazinyl, 4- methylpiperazinyl.pyrrolidinyl, morpholinyl, dihydro-pyrazolyl, dihydro-pyridyl, dihydropyranyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl,
  • benzimidazolyl benzotriazolyl, indolyl, benzo-1 ,3-dioxolyl, 2,3-dihydro-benzo[1 ,4]dioxinyl, indazolyl or benzothiadiazolyl, each of which is unsubstituted or mono-, di- or trisubstituted.
  • halogen refers to one or, where appropriate, a plurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (CI, chloro) or iodine (I, iodo) atoms.
  • fluorine fluorine
  • bromine Br, bromo
  • chlorine CI, chloro
  • iodine I, iodo
  • perhalogen refer respectively to two, three and four substituents, where each substituent can be selected independently from the group consisting of fluorine, chlorine, bromine and iodine.
  • Halogen preferably means a fluorine, chlorine or bromine atom.
  • Fluorine and chlorine are more preferred, particularly when the halogens are substituted on an alkyl (haloalkyl) or alkoxy group (e.g. CF 3 and CF 3 0). It shall be understood that the respective denotation of Hal is independently of one another in any radical of the invention.
  • R is preferably straight chain alkyl having 1 to 4 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH. More preferably R is methyl or ethyl, and most preferably methyl.
  • W is preferably N.
  • R 3 denotes preferably H, methyl, ethyl, 2-hydroxyethyl or 2-methoxyethyl.
  • the group S(0)(NR 3 ) is selected from
  • the group N(SO)R 3 is selected from
  • R'" and X have the meaning given above, it is preferably
  • R', X and Y have the meaning given above, it is preferably
  • A is especially preferred one of the following groups:
  • R 3 has the meaning given above and is preferably methyl, ethyl, 2-hydroxyethyl or 2- methoxyethyl.
  • R 5 , R 6 and R 7 are preferably independently H, S0 2 CH 3 , SO 2 CH 2 CH 3 , SO 2 CH 2 CH 2 OH,
  • R 8 is preferably a group selected from CON(SO)R 3' CH 3 , CON(SO)R 3 CH 2 CH 3 ,
  • R 3 is H or methyl.
  • X denotes preferably N or CH.
  • Y is preferably O or S.
  • R , R denote each independently preferably H, methyl or ethyl. More preferred are compounds of formula I, wherein both R , R are simultaneously H or wherein one of the groups is H and the other group is a straight chain or branched alkyl having 1 to 12 carbon atoms, more preferably methyl or ethyl.
  • T is preferably N or CH, most preferably N.
  • Z 1 is preferably S or NH.
  • Z 2 , Z 3 preferabyl denote independently CH or N.
  • Z 4 is preferably N or CH. is preferably S(0)(NR 3' ), N(SO)R 3' , more preferably
  • Z 6 is preferably CH 2 , CO or ⁇ R 3' R 3'
  • Z 7 is preferably CH 2 , S, O, NH. If Z 7 is S, O, NR 3' , t and q are each 1 or one of t and q is 1 while the other denotes 2. Most preferably, t and q simultaneously denote 1.
  • R , R , R , R and R is or contains a sulfoximine group selected from:
  • R '" , R "" , R 5 , R 6 , R 7 and R 8 is selected from a straight chain or branched alkyl group having 1 to 12 carbon atoms, wherein at least one CH 2 -group is replaced by the
  • R 3 , Z 7 , t, q are as defined above, and pharmaceutically usable derivatives, solvates, salts, prodrugs, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios and compounds of formula I, wherein one or more H atoms are replaced by D (deuterium).
  • Q is preferably selected from one of the following groups:
  • R , R , R , R and R is or contains a sulfoximine group selected from:
  • R '" , R "" , R 5 , R 6 , R 7 and R 8 is selected from a straight chain or branched alkyl group having 1 to 12 carbon atoms, wherein at least one CH 2 -group is replaced by the
  • X, Y, R , R “ , R “ , R 3' , R 7 , Z 5 , Z 6 , Z 7 , T, t, q are as defined above, and pharmaceutically usable derivatives, solvates, salts, prodrugs, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios and compounds of formula I, wherein one or more H atoms are replaced by D (deuterium).
  • T" is N , CH;
  • R 7 denotes straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3
  • R , R 3 , R 3 , R 4 , Hal, Het, Ar and Cyc are as defined above, and pharmaceutically usable derivatives, solvates, salts, prodrugs, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios and compounds of formula I , wherein one or more H atoms are replaced by D (deuterium).
  • R', R 7 and T' are as defined above, and pharmaceutically usable derivatives, solvates, salts, prodrugs, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios and compounds of formula I, wherein one or more H atoms are replaced by D (deuterium).
  • R 7 is as defined above, and pharmaceutically usable derivatives, solvates, salts, prodrugs, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios and compounds of formula I, wherein one or more H atoms are replaced by D (deuterium).
  • R 7 and T' are as defined above, and pharmaceutically usable derivatives, solvates, salts, prodrugs, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios and compounds of formula I, wherein one or more H atoms are replaced by D (deuterium).
  • R 7 is selected from the group of
  • R 7 is selected from the group of
  • the subject-matter of the invention relates to compounds of formula (I) as medicament, in which at least one of the aforementioned radicals has any meaning, particularly realize any preferred embodiment, as described above.
  • Radicals which are not explicitly specified in the context of any embodiment of formula (I), sub-formulae thereof or other radicals thereto, shall be construed to represent any respective denotations according to formula (I) as disclosed hereunder for solving the problem of the invention.
  • radicals may adopt all designated meanings as each described in the prior or following course of the present specification, irrespective of the context to be found, including, but not limited to, any preferred embodiments. It shall be particularly understood that any embodiment of a certain radical can be combined with any embodiment of one or more other radicals.
  • step c) reaction of the enantiomerically enriched or pure piperazine base obtained in step a) with the enantiomerically enriched or pure enantiomer of A/-((2-chloropyrimidin-5-yl)(methyl)(oxo)-A 6 - sulfanylidene)-2,2,2-trifluoroacetamide obtained in step b) in the presence of a base, isolation of the product thus obtained followed by its deprotection , to obtain the enantiomerically enriched or pure single diastereoisomer of (2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5- yl)(imino)(methyl)-A 6 -sulfanone.
  • step c) reaction of the enantiomerically enriched or pure piperazine base obtained in step a) with the enantiomerically enriched or pure enantiomer of A/-((2-chloropyrimidin-5-yl)(methyl)(oxo)-A 6 - sulfanylidene)-2,2,2-trifluoroacetamide obtained in step b) in the presence of a base, isolation of the product thus obtained followed by its deprotection , to obtain the enantiomerically enriched or pure single diastereoisomer of (2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5- yl)(imino)(methyl)-A 6 -sulfanone.
  • the chiral resolution agent D-di-p-anisoyltartaric acid used in steps a) of embodiments A and B above can be exchanged for D-di-p-toluyltartaric acid or (R)-(+)- chlocyphos to obtain the identical products.
  • Particularly highly preferred embodiments are those compounds of formula (I) listed in Table 1 and/or physiologically acceptable salts thereof.
  • Table 1 Compounds of formulae (I). OGA enzyme inhibition assay and % fraction unbound in mouse plasma
  • Activity range of the compounds of Formula (I) is the following:
  • Preferred compounds of the present invention demonstrate adequate properties for use as a drug.
  • such preferred compounds show a high solid state stability, high stability in the presence of liver microsome, high oxidation stability and suitable permeability.
  • Further preferred compounds of the present invention demonstrate their suitability as drugs by potent biological activity, such as the level of O-GlcNAcylation of total proteins measured in brain extracts. Relevant tests for determining such parameters are known by the person skilled in the art, e.g. solid state stability (Waterman K.C. (2007) Pharm Res 24(4); 780-790), stability in the presence of liver microsome (Obach R. S. (1999) Drug Metab Dispos 27(1 1 ); 1350-135) and the permeability (e.g.
  • the starting materials can also be formed in-situ by leaving them in the un- isolated status in the crude reaction mixture, but immediately converting them further into the compound according to the invention. On the other hand, it is possible to carry out the reaction stepwise.
  • the following abbreviations refer respectively to the definitions below:
  • the compounds according to Formula (I) and related formulae of this invention may be prepared from readily available starting materials. If such starting materials are not commercially available, they may be prepared by standard synthetic techniques. In general, the synthesis pathways for any individual compound of Formula (I) and related formulae will depend on the specific substituents of each molecule, such factors being appreciated by those having ordinary skill in the art. The following general methods and procedures described hereinafter in the examples may be employed to prepare compounds of Formula (I) and related formulae. Reaction conditions depicted in the following schemes, such as temperatures, solvents, or co-reagents, are given as examples only and are not restrictive. It will be appreciated that where typical or preferred experimental conditions (i.e.
  • reaction temperatures, time, moles of reagents, solvents etc. are given, other experimental conditions can also be used unless otherwise stated.
  • Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art, using routine optimisation procedures. For all the protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3 rd Edition 1999.
  • a “leaving group” LG denotes a chemical moiety which can be removed or replaced by another chemical group.
  • the term leaving group preferably denotes CI, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (preferably phenyl- or p- tolylsulfonyloxy).
  • LG When a leaving group LG is attached to an aromatic or heteroaromatic ring, LG can denote in addition S0 2 -alkyl or F. Radicals of this type for activation of the carboxyl group in typical acylation reactions are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg- Thieme-Verlag, Stuttgart). Activated esters are advantageously formed in situ, for example through addition of HOBt, N-hydroxysuccinimide or HATU. Depending on the nature of A, R, W, Q, m and n, different synthetic strategies may be selected for the synthesis of compounds of Formula (I). In the process illustrated in the following schemes, A, R, W, Q, m and n are as above-defined in the description unless otherwise mentioned.
  • Compound of formula (I) can be separated into compounds of formula (la) and (lb) by chiral chromatography or by chiral resolution, re-crystallization with use of an optically active acid, using methods known by one skilled in the art and as described below in the examples (Scheme 1 ).
  • This addition can be performed under thermic conditions, heating both compounds at a temperature between 50°C and 200 °C, using regular heating or microwave irradiation, in the presence of a base, such as but not limited to TEA, DIEA, K 2 C0 3 or Cs 2 C0 3 , in a polar solvent, e.g. DMF, DMA or NMP.
  • a base such as but not limited to TEA, DIEA, K 2 C0 3 or Cs 2 C0 3
  • a polar solvent e.g. DMF, DMA or NMP.
  • this addition can be catalysed by a metal complex, such as but not limited to PdCI 2 , Pd(OAc) 2 , Pd 2 (dba) 3 in the presence of a ligand, e.g. BINAP, o-Tol 3 P, X-Phos, and a base, e.g. NaOfBu, Cs 2 C0 3 or K 2 C0 3 , in a suitable solvent or solvent mixture, for example dioxane, Toluene/MeOH, at a temperature between RT to 150 °C, preferably at RT, for a few hours, e.g. one hour to 24 h (Scheme 2).
  • a metal complex such as but not limited to PdCI 2 , Pd(OAc) 2 , Pd 2 (dba) 3 in the presence of a ligand, e.g. BINAP, o-Tol 3 P, X-Phos, and a base, e.g.
  • Amine of formula (II) is obtained after deprotection of compound (IVa).
  • PG is a suitable protecting group, which is compatible with the chemistry described below, such as but not limited to BOC. It can be removed under acidic conditions, such as but not limited to HCI in MeOH or dioxane or TFA in DCM, yielding isolation of amine (II).
  • compound of formula (Id) can be obtained from compound (IVc) by displacement of the leaving group LG, as defined above, in the presence of a base such as but not limited to Cs 2 C0 3 in a polar solvent, e.g. DMF, DMSO or NMP (Scheme 3).
  • a base such as but not limited to Cs 2 C0 3 in a polar solvent, e.g. DMF, DMSO or NMP (Scheme 3).
  • compound of formula (Id) can be prepared by metal catalysed cross coupling reaction with a suitable boronic acid (Va) or ester (Vb) and an heterocycle of formula (III), using conditions known by a person skilled in the art, such as but not limited to Pd(PPh 3 ) 4 as catalyst, K 2 C0 3 as base, dioxane as solvent at temperature ranging from RT to 180 °C (Scheme 3). Hydrogenation of the resulting coupling product in the presence of a catalyst such as Pd(OH) 2 , would yield compound of formula (I .
  • a catalyst such as Pd(OH) 2
  • reductive amination can be performed in two steps, with first imine formation, that can be catalysed by Ti(OiPr) 4 , followed by reduction with suitable reducing agent, such as but not limited to NaBH 4 in MeOH (Abdel-Magid, A. F. at al. J. Org. Chem. 1996, 61, 3849-3862).
  • suitable reducing agent such as but not limited to NaBH 4 in MeOH (Abdel-Magid, A. F. at al. J. Org. Chem. 1996, 61, 3849-3862).
  • ketone (IX) can be reduced into the corresponding alcohol (VIII) using usual reductive agents such as NaBH 4 in an alcoholic solvent, such as MeOH.
  • Alcohol functionality can be then transformed into a suitable leaving group, such as but not limited to CI or OMs, using conditions known to a person skilled in the art.
  • the addition of amine (VI) to intermediate (VII) would yield the formation of compound (IV).
  • compound of formula (X), wherein W, Q, m and n are defined as above and PG is a suitable protecting group, such as but not limited to BOC, can be prepared from amine (XI), from compounds (XII), wherein m, n and PG are defined as above and Y 2 is an ester or a leaving group, or from compounds (XI I la) or (X 1Mb) (Scheme 5).
  • compound of formula (X) can be prepared by the addition of an amine of formula (XI) to a heterocycle of formula (III), where LG is a leaving group as defined above.
  • This addition can be performed under thermic conditions or can be catalysed by a metal complex, using conditions known by a person skilled in the art and as described below in the examples.
  • Different heterocycles Q can be prepared from ester functionality, such as but not limited to oxadiazole, thiadiazole and thiazole, (Jakopin, Z. ef al. Curr. Org. Chem. 2008, 12, 850-898. Hemming, K. Science of Synthesis, 2004, 13, 127-184. Augustine, J. K. et al. Tetrahedron, 2009, 65, 9989-9996. 37. Kempson, J.
  • a base such as but not limited to Cs 2 C0 3 in a polar solvent, e.g. DMF, DMSO or NMP.
  • Compound of formula (X), wherein Q is a thiazole can be obtained from compound (XII), wherein Y 2 is an aminomethanecarbothioyl group, and a suitable alpha-bromo ketone, using conditions know by a person skilled in the art.
  • compound of formula (X) can be prepared by metal catalysed cross coupling reaction with a suitable boronic acid (XI I la) or ester (XI I lb), and a heterocycle of formula (III), using conditions known by a person skilled in the art, such as but not limited to Pd(PPh 3 ) 4 as catalyst, K 2 C0 3 as base, dioxane as solvent at temperature ranging from RT to 180 °C (Scheme 5). Hydrogenation of the resulting coupling product in the presence of a catalyst such as Pd(OH) 2 , would yield compound of formula (X) (e.g. Andres, J.-l. ef al. J. Med. Chem. 2012, 55, 8685-8699) (Scheme 5).
  • a catalyst such as Pd(OH) 2
  • PG is a suitable protecting group, which is compatible with the chemistry described above, such as but not limited to BOC. It can be removed under acidic conditions, such as but not limited to HCI in MeOH or dioxane or TFA in DCM, yielding isolation of amine (XIV). It can be further transformed into compound of formula (I) by reductive alkylation with ketone of formula (IX), following conditions well known by a person skilled in the art, as described in the examples (Abdel-Magid, A. F. at al. J. Org. Chem. 1996, 61, 3849-3862). Alternatively, amine (XIV) addition to compound (VII), prepared as described above and in the examples, would yield the formation of compound of formula (I).
  • Amine of formula (II) can be separated into amines of formula (I I a) and (Mb) by chiral
  • amines of formula (lla) and (lib) can be synthesized from chiral amines (XVIa) and (XVIb) respectively.
  • Addition of amines (XVIa) and (XVIb) to reagent (XV), wherein PG is a protecting group, e.g. BOC or S0 2 Tol and LG is a leaving group, e.g. CI, would yield the formation of protected amines (IVe) and (IVf) respectively (Thiel, O. R. ef al. J. Org. Chem. 2008, 73, 3508- 3515).
  • Deprotection conditions need to be selected based on the nature of the PG, such as HCI in dioxane or MeOH or TFA in DCM for BOC protecting group.
  • a mixture of HBr, AcOH and 4-hydroxybenzoic acid or a mixture of H 2 S0 4 and trifluoroacetic acid at temperatures ranging from RT to 100°C would be used to cleave a sulfonamide protecting group, such as para-toluene sulfonamide.
  • ketone of formula (IX) can be transformed into chiral imine (XVIII), reacting with a chiral auxiliary, such as but not limited to tert- butanesulfinamide group in the presence of titanium ethoxide (Ellman J. A. et al. Acc. Chem. Res. 2002, 35, 984-995). It can be further transformed into sulfinamide (XVIIa) or (XVIIb), depending on the conditions used for the reduction step, as described in the reference from Ellman J. A. ef al. J. Org. Chem. 2007, 72, 626-629.
  • a chiral auxiliary such as but not limited to tert- butanesulfinamide group in the presence of titanium ethoxide
  • aldehyde of formula (XIX) can be transformed into alcohol of formula (VIII) with addition of a suitable nucleophile, such as but not limited to a Grignard reagent (Scheme 9).
  • a suitable nucleophile such as but not limited to a Grignard reagent (Scheme 9).
  • ketone of formula (IXa) can be obtained by Stille cross coupling reaction between aryl halide (XX) and tributyl(1-ethoxyvinyl)tin in the presence of a catalyst, such as but not limited to Pd(PPh 3 ) 2 CI 2 in toluene at temperatures ranging from RT to 1 10°C (Scheme 10).
  • a catalyst such as but not limited to Pd(PPh 3 ) 2 CI 2 in toluene at temperatures ranging from RT to 1 10°C (Scheme 10).
  • alternative metals such as but not limited to copper, iron, manganese or ruthenium complexes.
  • sulfoximines (XXV) (R 3 ⁇ H) can also be obtained by oxidation of sulfilimines (XXIII), which are accessible by imination of sulfides (XXI) or transformation of sulfoxides (XXII) (Frings, M. et al. Eur. J. Med. Chem. 2017, 126, 225-245 and cited references).
  • Sulfoximines (XXIV) or (XXV) can be separated into compounds of formula (XXIVa) and (XXIVb) or (XXVa) and (XXVb) by chiral chromatography or by chiral resolution, re-crystallization with use of an optically active acid, using methods known by one skilled in the art and as described below in the examples (Scheme 11 ).
  • sulfoxide (XXII) can be separated into compounds of formula (XXIIa) and (XXIIb) by chiral chromatography or by chiral resolution, using methods known by one skilled in the art and as described below in the examples (Scheme 1 1 ).
  • Chiral sulfoxide of formula (XXIIa) and (XXIIb) can be transformed into chiral sulfoximine of formula (XXIVa) and (XXIVb) respectively or (XXVa) and (XXVb) respectively.
  • Stereospecific transformation with retention of configuration can be achieved by rhodium-catalyzed imination and subsequent deprotection (H. Okamura et al. Organic Letters 2004, 6, 1305-1307) or imination with ammonium carbamate and Phl(OAc) 2 in MeOH, affording directly (XXIVa) and (XXIVb) (M. Zenzola ef al. Angew. Chem. Int. Ed. 2016, 55, 7203 -7207).
  • the main routes to chiral sulfoxides are depicted in Scheme 12.
  • the resolution of a racemic mixture (route i) is one possible method used to produce chiral sulfoxides, by either a chemical approach or an enzymatic reaction. Transformation of a diastereochemically pure sulfinate is an alternative route affording sulfoxides with high enantiomeric excess (ee) values (route ii).
  • the enantioselective oxidation of prochiral sulfides (XXI) by enzymatic or non-enzymatic methods represents a relatively direct way (route iii) to prepare enantioenriched sulfoxides.
  • Another preparative method (route iv) is to modify the structure of some chiral sulfoxides without any loss of stereochemistry at the sulfur atom (Organosulfur chemistry in asymmetric synthesis, Takeshi Toru ; 2008).
  • a metal such as but not limited to Ti(/-PrO) 4
  • a chiral ligand selected from diethyl tartrate, madelic acid, binaphthol, dibromo- binaphthol, hydrobenzoin, or any other ligand known by a persone skilled in the art
  • an oxidant such as but not limited to cumene hydroperoxide, fert-butyl hydroperoxide, H 2 0 2 , with the optional addition of water or a tertiary amine, such as /-Pr 2 NEt, N-methylmorpholine or 1 ,4-dimethyl- piperazine (G.
  • kinetic resolution of sulfoxide of formula (XXII) into sulfone (XXVI) can be achieved under similar conditions and according to well-known methods, leaving one enantioenriched sulfoxide unchanged (G. E. O'Mahony et al. Arkivoc 2011 (i) 1-1 10).
  • a suitable base might be selected from metal oxides, e.g. aluminum oxide, alkaline metal hydroxide (potassium hydroxide, sodium hydroxide and lithium hydroxide, inter alia), alkaline earth metal hydroxide (barium hydroxide and calcium hydroxide, inter alia), alkaline metal alcoholates (potassium ethanolate and sodium propanolate, inter alia), alkaline metal carbonates (e.g., sodium bicarbonate) and several organic bases (e.g., A/,A/-diisopropylethylamine, piperidine or diethanolamine, inter alia).
  • metal oxides e.g. aluminum oxide, alkaline metal hydroxide (potassium hydroxide, sodium hydroxide and lithium hydroxide, inter alia), alkaline earth metal hydroxide (barium hydroxide and calcium hydroxide, inter alia), alkaline metal alcoholates (potassium ethanolate and sodium propanolate, inter alia), alkaline metal carbonates (e.g
  • the reaction is generally carried out in an inert solvent.
  • suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1 ,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert- butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacet
  • the reaction time is between a few minutes and 14 days
  • the reaction temperature is between about -80°C and 140°C, normally between -50°C and 120°C, preferably between -20°C and 100°C.
  • the compounds of formula (I) and sub-formulae thereof are accessible via the routes above.
  • the starting materials are usually known to the skilled artisan, or they can be easily prepared by known methods.
  • the compounds of formula (I) can be modified, like hydrogenated or metal-reduced, to remove the chlorine, or put into a substitution reaction, and/or to be transformed with an acid or base into a salt, preferably with a strong acid.
  • Time will also be adjusted from minutes to several hours or even over night.
  • alkylation, ether formation, ester formation, amide formation are known to the one skilled in the art.
  • Arylation with aryl boronic acids can be performed in presence of a Pd catalyst, appropriate ligand and base, preferably a carbonate, phosphate, borate salt of sodium, potassium or cesium.
  • Organic bases like Et 3 N, DIPEA or the more basic DBU can also be used.
  • Solvents can vary too, from toluene, dioxane, THF, diglyme, monoglyme, alcohols, DMF, DMA, NMP, acetonitrile, in some cases even water, and others.
  • Pd (PPh 3 ) 4 or Pd(OAc) 2
  • PdCI 2 type precursors of PdO catalysts have advanced to more complex ones with more efficient ligands.
  • aryl-trifluoroborate potassium salts instead of boronic acids and esters, aryl-trifluoroborate potassium salts (Suzuki-Miyaura coupling), organo silanes (Hiyama coupling), Grignard reagents (Kumada), organozinc compounds (Negishi coupling) and stannanes (Stille coupling) may be useful. This experience can be transferred to N- and O-arylations.
  • a salt of the compounds preferably those of formula (I)
  • the said compounds according to the invention can be used in their final non- salt form.
  • the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art.
  • Pharmaceutically acceptable salt forms of the compounds according to the invention are for the most part prepared by conventional methods.
  • one of its suitable salts can be formed by the reaction of the compound with a suitable base to give the corresponding base-addition salt.
  • bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides, such as magnesium hydroxide, calcium hydroxide and barium hydroxide; alkali metal alkoxides, for example potassium ethoxide and sodium propoxide; and various organic bases, such as piperidine, diethanolamine and N-methyl-glucamine (meglumine), benzathine, choline, diethanolamine, ethylenediamine, benethamine, diethylamine, piperazine, lysine, L-arginine, ammonia,
  • alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide
  • alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and barium hydroxide
  • alkali metal alkoxides
  • acid-addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and corresponding salts thereof, such as sulfate, nitrate or phosphate and the like, and alkyl- and monoarylsulfonates, such as methanesulfonate, ethanesulfonate, toluenesulfonate and
  • pharmaceutically acceptable organic and inorganic acids for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and corresponding salts thereof, such as sulfate, nitrate or phosphate and the like, and alkyl- and monoarylsulfonates, such as methanesulfonate, ethanesulfonate, toluenesulfonate and
  • benzenesulfonate and other organic acids and corresponding salts thereof, such as carbonate, acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like.
  • pharmaceutically acceptable acid-addition salts of the compounds according to the invention include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprate, caprylate, chloride, chlorobenzoate, citrate, cyclamate, cinnamate,
  • cyclopentanepropionate digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, glycolate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate,
  • Both types of salts may be formed or interconverted preferably using ion-exchange resin techniques.
  • pharmaceutically acceptable salt and “physiologically acceptable salt”, which are used interchangeable herein, in the present connection are taken to mean an active ingredient which comprises a compound according to the invention in the form of one of its salts, in particular if this salt form imparts improved
  • the pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.
  • the above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, me-glumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tro-meth-amine, but this is not intended to represent a restriction.
  • the acid-addition salts of basic compounds of the formula (I) are prepared by bringing the free base form into contact with a sufficient amount of the desired acid, causing the formation of the salt in a conventional manner.
  • the free base can be regenerated by bringing the salt form into contact with a base and isolating the free base in a conventional manner.
  • the free base forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts other-wise correspond to the respective free base forms thereof.
  • the pharmaceutically acceptable base-addition salts of the compounds of the formula I are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines.
  • metals are sodium, potassium, magnesium and calcium.
  • Preferred organic amines are ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, choline, diethanol-amine, ethylenediamine, N-methyl-D-glucamine and procaine. This is not intended to represent a restriction.
  • the base-addition salts of acidic compounds of the formula I are prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conventional manner.
  • the free acid can be regenerated by bringing the salt form into contact with an acid and isolating the free acid in a conventional manner.
  • the free acid forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts other-wise correspond to the respective free acid forms thereof.
  • a compound of the formula (I) contains more than one group which is capable of forming pharmaceutically acceptable salts of this type, the formula I also encompasses multiple salts.
  • Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, di-phosphate, disodium and trihydrochloride, but this is not intended to represent a restriction.
  • the pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.
  • the compounds of the formula (I) can be chiral and can accordingly occur in various enantiomeric forms. They can therefore exist in racemic or in optically active form.
  • the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers.
  • the end product or even the Intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis.
  • diastereomers are formed from the mixture by reaction with an optically active resolving agent.
  • suitable resolving agents are optically active acids, such as the (R) and (S) forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, di-O-p- toluoyl-tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N-benzenesulfonylproline), or the various optically active acids, such as the (R) and (S) forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, di-O-p- toluoyl-tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N-benzenesulfonylproline), or the various optically active
  • optically active acids such as the (R) and (S) forms of tartaric acid, di
  • the suitably formed salt with optically active acid is crystallized using various combinations of solvents, such as but not limited to methanol, ethanol, isopropanol, THF, water, diethyl ether, acetone, methyl tert-butyl ethers and other solvents known to the person skilled in the art.
  • solvents such as but not limited to methanol, ethanol, isopropanol, THF, water, diethyl ether, acetone, methyl tert-butyl ethers and other solvents known to the person skilled in the art.
  • an optically active resolving agent for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatised methacrylate polymers immobilised on silica gel.
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/ acetonitrile, for example in the ratio 82:15:3.
  • aqueous or alcoholic solvent mixtures such as, for example, hexane/isopropanol/ acetonitrile, for example in the ratio 82:15:3.
  • a further aspect of the invention relates to the use of compounds according to formula (I) and/or physiologically acceptable salts thereof for inhibiting a glycosidase.
  • Such use may be therapeutic or non-therapeuic in character.
  • the term “inhibition” denotes any reduction in glycosidase activity, which is based on the action of the specific inventive compounds capable to interact with the target glycosidase in such a manner that makes recognition, binding and blocking possible. It shall be understood that the compounds of the invention finally interact with the target to unfold the effect.
  • the compounds are characterized by such an appreciable affinity to at least one glycoside hydrolase which ensures a reliable binding and preferably a complete blocking of glycosidase activity.
  • the substances are mono-specific in order to guarantee an exclusive and directed recognition with the chosen single glycosidase target.
  • recognition without being limited thereto - relates to any type of interaction between the specific compounds and the target, particularly covalent or non-covalent binding or association, such as a covalent bond, hydrophobic/ hydrophilic interactions, van der Waals forces, ion pairs, hydrogen bonds, ligand-receptor interactions, and the like. Such association may also encompass the presence of other molecules such as peptides, proteins or nucleotide sequences.
  • the present receptor/ligand-interaction is preferably characterized by high affinity, high selectivity and minimal or even lacking cross-reactivity to other target molecules to exclude unhealthy and harmful impacts to the treated subject.
  • the glycosidase comprises glycoside hydrolases, more preferably family 84 glycoside hydrolases, most preferably O-glycoprotein-2- acetamido-2deoxy- -D-glucopyranosidase (OGA), highly preferably a mammalian O-GlcNAcase.
  • OAA O-glycoprotein-2- acetamido-2deoxy- -D-glucopyranosidase
  • O-GlcNAcase highly preferably a mammalian O-GlcNAcase.
  • the compounds of formula (I) according to the invention selectively bind an O-GlcNAcase, e.g. thereby selectively inhibiting the cleavage of 2-acetamido-2-deoxy- -D- glucopyranoside (O-GlcNAc) while they do not substantially inhibit a lysosomal ⁇ -hexosaminidase.
  • the compounds according to the invention preferably exhibit an advantageous biological activity, which is easily demonstrated in enzyme activity assays as described herein or known from prior art. In such in-vitro assays, the compounds preferably exhibit and cause an inhibitory effect.
  • IC 50 is the concentration of a compound that produces 50 % of the maximal inhibition for that compound.
  • the glycosidase target is especially half inhibited by the compounds described herein if the
  • concentration of the compounds amounts to less than 100 ⁇ , preferably less than 10 ⁇ , more preferably less than 1 ⁇ , most preferably less than 0.2 ⁇ . Most preferably, compounds of Formula (I) exhibit an IC 50 less than 0.02 ⁇ .
  • a further aspect of the present invention relates to a method for inhibiting a glycosidase, wherein a system capable of expressing the glycosidase, particularly expressing said glycosidase, is contacted with at least one compound of formula (I) according to the invention and/or
  • the glycosidase is contacted with a compound selectively inhibiting O-GlcNAcase and more preferably having an IC 50 of less than 0.2 ⁇ . It is also preferred that the method is performed in-vitro and/or that the method is not practiced on the human body.
  • a cellular system is preferred in the scope of the method. The cellular system is defined to be any subject provided that the subject comprises cells. The cell refers to any type of primary cells or genetically engineered cells, whether in the isolated status, in culture, as cell line, assembled in tissue, organs or intact laboratory mammals, provided that they are capable of expressing the glycosidase.
  • the cell expresses the glycosidase as inherent pre- condition to put the methods of inhibition into practice.
  • the cells are capable of expressing or do express the glycosidase, it shall not be excluded that glycosidase-deficient cells can be used and the glycosidase is artificially added to the cellular system.
  • the assay of the invention can be even completely performed in-vitro such that the cell is waived but a glycosidase is contacted with at least one compound of formula (I) according to the invention and/or physiologically acceptable salts thereof. Hence, an amount of isolated glycosidase is provided in crude or purified form for this purpose.
  • the glycosidase-signaling pathways are relevant for various diseases, preferably neurodegenerative diseases, diabetes, cancer, cardiovascular diseases and stroke. Accordingly, the compounds according to the invention are useful in the prophylaxis and/or treatment of diseases that are dependent on the said signaling pathways by interaction with one or more of them.
  • the present invention therefore relates to the therapeutic and non-therapeutic use of compounds according to the invention as inhibitors of the signaling pathways described herein, preferably of the OGA-mediated signaling.
  • the method of the invention can be performed either in-vitro or in-vivo.
  • the susceptibility of a particular cell to treatment with the compounds according to the invention can be particularly determined by in-vitro tests, whether in the course of research or clinical application.
  • a culture of the cell is combined with a compound according to the invention at various locations.
  • concentrations for a period of time which is sufficient to allow the active agents to modulate glycosidase activity usually between about one hour and one week.
  • In-vitro treatment can be carried out using cultivated cells from any sample or cell line.
  • the host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc.
  • Animal models are of interest for experimental investigations, providing a model for treatment of human disease.
  • various scientists have developed suitable models or model systems, for example cell culture models and models of transgenic animals.
  • interacting compounds can be utilized in order to modulate the signal.
  • the compounds according to the invention can also be used as reagents for testing OGA-dependent signal transduction pathways in animals and/or cell culture models or in the clinical diseases mentioned in this application.
  • the use according to the previous paragraphs of the specification may be either performed in-vitro or in-vivo models.
  • the inhibition can be monitored by the techniques described in the course of the present specification.
  • the in-vitro use is preferably applied to samples of humans suffering from neurodegenerative diseases, diabetes, cancer, cardiovascular diseases and stroke. Testing of several specific compounds and/or derivatives thereof makes the selection of that active ingredient possible that is best suited for the treatment of the human subject.
  • the in-vivo dose rate of the chosen derivative is advantageously pre-adjusted to the glycosidase susceptibility and/or severity of disease of the respective subject with regard to the in-vitro data. Therefore, the therapeutic efficacy is remarkably enhanced.
  • a further aspect of the invention relates to a medicament comprising at least one compound according to the invention and/or pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
  • a “medicament” in the meaning of the invention is any agent in the field of medicine, which comprises one or more compounds of formula (I) or preparations thereof (e.g. a pharmaceutical composition or pharmaceutical formulation) and can be used in prophylaxis, therapy, follow-up or aftercare of patients who suffer from diseases, which are associated with OGA activity, in such a way that a pathogenic modification of their overall condition or of the condition of particular regions of the organism could establish at least temporarily.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient an effective amount of at least one compound of formula (I) according to the invention and/or physiologically acceptable salts thereof together with pharmaceutically tolerable adjuvants and/or excipients.
  • an "adjuvant” denotes every substance that enables, intensifies or modifies a specific response against the active ingredient of the invention if administered simultaneously, contemporarily or sequentially.
  • Known adjuvants for injection solutions are, for example, aluminum compositions, such as aluminum hydroxide or aluminum phosphate, saponins, such as QS21 , muramyldipeptide or muramyltripeptide, proteins, such as gamma-interferon or TNF, M59, squalen or polyols.
  • the active ingredient may be administered alone or in combination with other treatments.
  • a synergistic effect may be achieved by using more than one compound in the pharmaceutical composition, i.e. the compound of formula (I) is combined with at least another agent as active ingredient, which is either another compound of formula (I) or a compound of different structural scaffold.
  • the active ingredients can be used either simultaneously or sequentially.
  • the present compounds are suitable for combination with agents known to those of skill in the art (e.g., WO 2008/025170) and are useful with the compounds of the invention.
  • a compound according to the invention, or for use according to the invention may be provided in combination with any other active agents or pharmaceutical compositions where such combined therapy may be useful to modulate O-GlcNAcase activity, for example to treat neurodegenerative, inflammatory, cardiovascular, or immunoregulatory diseases or any condition described herein.
  • a compound according to the invention, or for use according to the invention may be provided in combination with one or more agents useful in the prevention or treatment of tauopathies and Alzheimer's disease. Examples of such agents may include, without limitation,
  • AChEls Acetylcholine esterase inhibitors
  • Aricept® Donepezil
  • NMDA antagonists such as memantine (Axura®, Ebixa®), Huperzine A, Phenserine, Debio-9902 SR (ZT-1 SR), Zanapezil (TAK0147), ganstigmine, NP7557, a7 nicotinic acetylcholine receptor agonists, 5-HT6 receptor antagonists, M1 muscarinic acetylcholine receptor agonists and positive allosteric modulators, etc
  • Tau aggregation inhibitors such as methylene blue, etc - Agents blocking tau aggregation seeding and propagation such as tau antibodies and tau vaccines, etc
  • Microtubule stabilizers such as AL-108, AL-208, paclitaxel, etc
  • a ⁇ Amyloid- ⁇ (A ⁇ ) peptide lowering agents such as ⁇ -secretase (BACE-1 ) inhibitors, senile plaque-clearing biologies such as ⁇ antibodies and ⁇ vaccines
  • the invention also relates to a set (kit) consisting of separate packs of an effective amount of a compound according to the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further medicament active ingredient.
  • the set comprises suitable containers, such as boxes, individual bottles, bags or ampoules.
  • the set may, for example, comprise separate ampoules, each containing an effective amount of a compound according to the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further medicament active ingredient in dissolved or lyophilized form.
  • compositions can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intra- dermal) methods.
  • oral including buccal or sublingual
  • rectal including buccal or sublingual
  • nasal including buccal, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, intramuscular, intravenous or intra- dermal
  • the pharmaceutical composition of the invention is produced in a known way using common solid or liquid carriers, diluents and/or additives and usual adjuvants for pharmaceutical engineering and with an appropriate dosage.
  • the amount of excipient material that is combined with the active ingredient to produce a single dosage form varies depending upon the host treated and the particular mode of administration.
  • Suitable excipients include organic or inorganic substances that are suitable for the different routes of administration, such as enteral (e.g. oral), parenteral or topical application, and which do not react with compounds of formula (I) or salts thereof.
  • suitable excipients are water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates, e.g.
  • compositions adapted for oral administration can be administered as separate units, such as, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • compositions adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise suspension media and thickeners.
  • the formulations can be administered in single-dose or multi-dose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilized) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary.
  • Injection solutions and suspensions prepared in accordance with the recipe can be prepared from sterile powders, granules and tablets.
  • formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, formulations which are suitable for oral administration may comprise flavors.
  • the pharmaceutical composition is adapted for oral administration.
  • the preparations can be sterilized and/or can comprise auxiliaries, such as carrier proteins (e.g. serum albumin), lubricants, preservatives, stabilizers, fillers, chelating agents, antioxidants, solvents, bonding agents, suspending agents, wetting agents, emulsifiers, salts (for influencing the osmotic pressure), buffer substances, colorants, flavorings and one or more further active substances, for example one or more vitamins.
  • auxiliaries such as carrier proteins (e.g. serum albumin), lubricants, preservatives, stabilizers, fillers, chelating agents, antioxidants, solvents, bonding agents, suspending agents, wetting agents, emulsifiers, salts (for influencing the osmotic pressure), buffer substances, colorants, flavorings and one or more further active substances, for example one or more vitamins.
  • Additives are well known in the art, and they are used in a variety of formulations.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient an effective amount of at least one compound of formula (I) according to the invention and/or physiologically acceptable salts thereof together with pharmaceutically tolerable adjuvants for oral administration, optionally in combination with at least another active pharmaceutical ingredient.
  • an amount of the pharmaceutical compound having a prophylactically or therapeutically relevant effect on a disease or pathological conditions i.e. which causes in a tissue, system, animal or human a biological or medical response which is sought or desired, for example, by a researcher or physician.
  • a “prophylactic effect” reduces the likelihood of developing a disease or even prevents the onset of a disease.
  • a “therapeutically relevant effect” relieves to some extent one or more symptoms of a disease or returns to normality either partially or completely one or more
  • therapeutically effective amount denotes an amount which, compared with a corresponding subject who has not received this amount, has the following consequence: improved treatment, healing, prevention or elimination of a disease, syndrome, condition, complaint, disorder or side-effects or also the reduction in the advance of a disease, complaint or disorder.
  • therapeutically effective amount also encompasses the amounts which are effective for increasing normal physiological function.
  • the respective dose or dosage range for administering the pharmaceutical composition according to the invention is sufficiently high in order to achieve the desired prophylactic or therapeutic effect of reducing symptoms of the aforementioned diseases.
  • the specific dose level, frequency and period of administration to any particular human will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general state of health, gender, diet, time and route of administration, rate of excretion, drug combination and the severity of the particular disease to which the specific therapy is applied.
  • the exact dose can be determined by one of skill in the art as a matter of routine experimentation.
  • the prior teaching of the present specification is valid and applicable without restrictions to the pharmaceutical composition comprising the compounds of formula (I) if expedient.
  • compositions can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit.
  • concentration of the active ingredient can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit.
  • prophylactically or therapeutically active ingredient in the formulation may vary from about 0.1 to 100 wt %.
  • the compound of formula (I) or the pharmaceutically acceptable salts thereof are administered in doses of approximately 0.5 to 1000 mg, more preferably between 1 and 700 mg, most preferably 5 and 100 mg per dose unit. Generally, such a dose range is appropriate for total daily incorporation. In other terms, the daily dose is preferably between approximately 0.02 and 100 mg/kg of body weight.
  • the specific dose for each patient depends, however, on a wide variety of factors as already described in the present specification (e.g. depending on the condition treated, the method of administration and the age, weight and condition of the patient).
  • Preferred dosage unit formulations are those which comprise a daily dose or part-dose, as indicated above, or a corresponding fraction thereof of an active ingredient.
  • pharmaceutical formulations of this type can be prepared using a process which is generally known in the pharmaceutical art.
  • an effective amount of a compound according to the invention for the treatment of neurodegenerative diseases is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day.
  • the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as a single dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same.
  • An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound according to the invention per se. It can be assumed that similar doses are suitable for the treatment of other conditions mentioned above.
  • the pharmaceutical composition of the invention can be employed as medicament in human and veterinary medicine.
  • the compounds of formula (I) and/or physiologically salts thereof are suited for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or propagated by OGA activity.
  • the diseases are neurodegenerative diseases, diabetes, cancer, cardiovascular diseases and stroke, more preferably neurodegenerative diseases, most preferably one or more tauopathies, highly preferably Alzheimer's disease and dementia.
  • the host of the compound is included in the present scope of protection according to the present invention.
  • Another aspect of the present invention relates to compounds of formula (I) according to the invention and/or physiologically acceptable salts thereof for use in the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or propagated by OGA activity.
  • Another aspect of the invention concerns compounds of formula (I) according to the invention and/or physiologically acceptable salts thereof for use in the prophylactic or therapeutic treatment and/or monitoring of neurodegenerative diseases, diabetes, cancer, cardiovascular diseases and stroke.
  • the prior teaching of the present specification concerning the compounds of formula (I), including any preferred embodiment thereof, is valid and applicable without restrictions to the compounds according to formula (I) and their salts for use in the prophylactic or therapeutic treatment and/or monitoring of neurodegenerative diseases, diabetes, cancer, cardiovascular diseases and stroke.
  • Another aspect of the invention relates to a method for treating a disease that is caused, mediated and/or propagated by OGA activity, wherein an effective amount of at least one compound of formula (I) according to the invention and/or physiologically acceptable salts thereof is administered to a mammal in need of such treatment.
  • Another aspect of the invention relates to a method for treating neurodegenerative diseases, diabetes, cancer, cardiovascular diseases and stroke, preferably a tauopathy, wherein an effective amount of at least one compound of formula (I) according to the invention and/or physiologically acceptable salts thereof is administered to a mammal in need of such treatment.
  • the preferred treatment is an oral administration.
  • the prior teaching of the invention and its embodiments is valid and applicable without restrictions to the methods of treatment if expedient.
  • the neurodegenerative disease or condition is more preferably selected from the group of one or more tauopathies and Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis with cognitive impairment (ALSci), Argyrophilic grain disease, Behavior variant frontotemporal dementia (bvFTD), Bluit disease, Corticobasal degeneration (CBP), Dementia pugilistica, Dementia with Lewy Bodies, Diffuse neurofibrillary tangles with calcification, Down's syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Frontotemporal Lobar Degeneration (FTLD), Ganglioglioma, Gangliocytoma, Gerstmann-Straussler-Scheinker disease, Globular glial tauopathy, Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1
  • the invention also relates to the use of compounds according to formula (I) and/or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or propagated by OGA activity. Furthermore, the invention relates to the use of compounds according to formula (I) and/or physiologically acceptable salts thereof for the production of a medicament for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or propagated by OGA activity.
  • Compounds of formula (I) and/or a physiologically acceptable salt thereof can furthermore be employed as intermediate for the preparation of further medicament active ingredients.
  • the medicament is preferably prepared in a non-chemical manner, e.g. by combining the active ingredient with at least one solid, fluid and/or semi-fluid carrier or excipient, and optionally in conjunction with a single or more other active substances in an appropriate dosage form.
  • the compounds of formula (I) according to the invention can be administered before or following an onset of disease once or several times acting as therapy.
  • the aforementioned compounds and medical products of the inventive use are particularly used for the therapeutic treatment.
  • a therapeutically relevant effect relieves to some extent one or more symptoms of a disorder, or returns to normality, either partially or completely, one or more physiological or biochemical parameters associated with or causative of a disease or pathological condition.
  • Monitoring is considered as a kind of treatment provided that the compounds are administered in distinct intervals, e.g. in order to booster the response and eradicate the pathogens and/or symptoms of the disease completely. Either the identical compound or different compounds can be applied.
  • the medicament can also be used to reducing the likelihood of developing a disorder or even prevent the initiation of disorders associated with OGA activity in advance or to treat the arising and continuing symptoms.
  • the disorders as concerned by the invention are preferably
  • prophylactic treatment is advisable if the subject possesses any preconditions for the aforementioned physiological or pathological conditions, such as a familial disposition, a genetic defect, or a previously passed disease.
  • compounds of formula (I) are provided for the first time.
  • the low molecular weight compounds of the invention are strong and selective glycosidase inhibitors with improved passive permeability.
  • the compounds of formula (I) have been shown to be competitive with PUGNAc, a known OGA inhibitor that binds in the substrate pocket.
  • the endogenous substrate is an O-GlcNAcylated protein.
  • O-GlcNAcylation of nuclear and cytoplasmic proteins is one of the most common post-translational modifications in animals and plants.
  • O- GlcNAc cycling modulates a number of cellular processes, and evidence is mounting that dysregulation of O-GlcNAcylation plays a role in the etiology of several diseases, including tauopathies and Alzheimer's disease.
  • O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) are the two enzymes that regulate O-GlcNAc cycling. Emerging data suggest that inhibitors that block OGA may help maintain healthy O-GlcNAc levels in tauopathies and Alzheimer's disease patients and thereby inhibit the formation of neurofibrillary tangles.
  • the current invention comprises the use of compounds of formula (I) in the regulation, modulation and/or inhibition of the
  • glycosidase signal cascade which can be advantageously applied as research tool, for diagnosis and/or in treatment of any disorders that are responsive to OGA signaling and inhibition.
  • the low molecular weight inhibitors can be applied either themselves and/or in combination with physical measurements for diagnostics of treatment effectiveness.
  • Medicaments and others can be applied either themselves and/or in combination with physical measurements for diagnostics of treatment effectiveness.
  • compositions containing said compounds and the use of said compounds to treat glycosidase-mediated conditions is a promising, novel approach for a broad spectrum of therapies causing a direct and immediate improvement in the state of health, whether in man and animal.
  • the impact is of special benefit to efficiently combat tauopathies and Alzheimer's disease, either alone or in combination with other neurodegenerative treatments.
  • the compounds of the invention can be advantageously administered at lower doses compared to other less potent or selective inhibitors of prior art while still achieving equivalent or even superior desired biological effects.
  • such a dose reduction advantageously leads to less or even no medicinal adverse effects.
  • the compounds of formula (I), their salts, isomers, tautomers, enantiomeric forms, diastereomers, racemates, derivatives, prodrugs and/or metabolites are characterized by a high specificity and stability, low manufacturing costs and convenient handling. These features form the basis for a reproducible action, wherein the lack of cross-reactivity is included, and for a reliable and safe interaction with the target structure.
  • the compounds according to Formula (I) can be prepared from readily available starting materials by several synthetic approaches, using both solution-phase and solid-phase chemistry protocols or mixed solution and solid phase protocols. Examples of synthetic pathways are described below in the examples. All reported yields are non optimized yields. Unless otherwise stated, compounds of Formula (I) and related formulae obtained as a racemic mixture can be separated to provide an enantiomerically enriched mixture or a pure enantiomer.
  • Method A Method: A-0.1 % TFA in H 2 0, B-0.1 % TFA in ACN; flow rate: 2.0 mL/min; column: XBridge C8 (50 x 4.6 mm, 3.5 pm), +ve mode
  • Method B Method: A-10 mM NH 4 HCO 3 in H 2 0, B- ACN; flow rate: 1.0 mL/min; column: XBridge C8 (50 x 4.6 mm, 3.5 pm), +ve mode
  • Method C Method: A-0.1 % HCOOH in H 2 0, B-ACN; flow rate: 1.5ml/min ; column: ZORBAX Eclipse XDB-C18 (50 x 4.6 mm, 3.5 pm), +ve mode
  • Method A Method: A-0.1 % TFA in H 2 0, B-0.1 % TFA in ACN; flow rate: 2.0 mL/min; column: XBridge C8 (50 x 4.6 mm, 3.5 pm).
  • Method B Method: A-10 mM NH 4 HCO 3 in H 2 0, B-ACN; flow rate: 1.0 mL/min; column: XBridge C8 (50 x 4.6 mm, 3.5 pm).
  • Method A Mobile Phase: 0.1 % DEA in n-Hexane: EtOH: 60:40; flow rate: 1.0ml_/min; column: Chiralcell OD-H (250 x 4.6 mm, 5 ⁇ ).
  • Ratio between C0 2 and co-solvent is ranging between 50:50 and 90:10
  • Method A Mobile Phase: 20 mM ammonia in IPA, flow rate: 4 mL/min; column: Chiralpak ADH (250 x 4.6 mm, 5 ⁇ ).
  • Method B Mobile Phase: 20 mM ammonia in methanol, flow rate: 10 mL/min; column: YMC Cellulose C (250 x 4.6 mm, 5 ⁇ ).
  • Method C Mobile Phase: 20 mM ammonia in IPA, flow rate: 4 mL/min; column: Lux A1 (250 x 4.6 mm, 5 ⁇ ).
  • Method D Mobile Phase: 20mM ammonia in MeOH, flow rate: 4 mL/ min; column: Chiralpak ADH (250 x 4.6 mm, 5 ⁇ ).
  • Method E Mobile Phase: IPA, flow rate: 3 mL/min; column: Lux A1 (250 x 4.6 mm, 5 ⁇ ).
  • Method A A-0.1 % TFA in H 2 0, B-MeOH or CAN; column: Sunfire C8 (19 x 250 mm, 5 ⁇ ) or Sunfire C18 (30 x 250 mm, 10 ⁇ ).
  • Method B A-10 mM NH 4 HC0 3 in H 2 0, B-MeOH or ACN, Column: Sunfire C8 (19 x 250 mm, 5 ⁇ ) or Sunfire C18 (30 x 250 mm, 10 ⁇ ).
  • Ratio between C0 2 and co-solvent is ranging between 50:50 and 90:10
  • Method A Mobile Phase: 20 mM ammonia in IPA; flow rate: 3 mL/min; column: Chiralpak ADH (250 x 30 mm, 5 ⁇ ).
  • Method B Mobile Phase: 20 mM ammonia in methanol; flow rate: 5 mL/min; column: YMC Cellulose C (250 x 30 mm, 5 ⁇ ).
  • Method C Mobile Phase: 20 mM ammonia in IPA; flow rate: 5 mL/min; column: Lux A1 (250 x 30 mm, 5 ⁇ ).
  • Method D Mobile Phase: 20mM ammonia in MeOH; flow rate: 4 mL/ min; column: Chiralpak ADH (250 x 30 mm, 5 ⁇ ).
  • Method E Mobile Phase: IPA, flow rate: 100 mL/min; column: Phenomenex Lux Amylose-1 (250 x 30 mm, 5 ⁇ ).
  • the microwave chemistry was performed on a single mode microwave reactor InitiatorTM Sixty from Biotage.
  • Step 5 6-(1 -chloroethyl)-2, 3-dihydroben
  • Step 6 tert-butyl 4-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate
  • the reaction mixture was then filtered and washed with 1 , 4 dioxane (200 ml), EtOAc (200 mL), acetonitrile (200 mL) and diethyl ether (200 mL).
  • the obtained solid was dissolved in water (350 mL) and washed with EtOAc (3 x 300 mL).
  • the combined organic layer was dried over Na 2 S0 4 , filtered and concentrated under vacuum.
  • the solid was refluxed in methanol containing 5% of water 12 V (1.2 L). The mixture was allowed to cool to RT and stirred overnight before the solid was collected by filtration and washed twice with 5% of water in methanol (2 x 1.0 L). The optical purity of the solid was 94% ee. The solid was again dissolved in refluxing methanol containing 5% of water (1.2 L). The mixture was allowed to cool to RT and stirred overnight before the solid was collected by filtration and washed with 5% of water in methanol (1.2 L). The optical purity of the solid was 97.94% ee (enantiomeric purity: 98.9%).
  • Step 2 5-bromo-2-(2-methylallyl) phenol and 3-bromo-2-(2-methylallyl) phenol
  • Step 6 6-(1 -chloroethyl)-2, 2-dimethyl-2, 3-dihydrobenzofuran
  • Step 7 tert-butyl 4-(1-(2, 2-dime thyl)piperazine-1-carboxylate
  • Step 8 1-(1-(2,2-dimethyl-2,3 zine dihydrochloride
  • Step 2 Mixture of 1 -(4-allyl-3-hydroxyphenyl) ethan-1-one and 1 -(2-allyl-3-hydroxyphenyl) ethan-1- one
  • Step 3 1 -(2-methyl-2,3-dihydrobenzofuran-6-yl)ethan-1 -one (Isomer A) and 1 -(2-methyl-2, 3- dihydrobenzofuran-4-yl)
  • Step 4 1 -(2-methyl-2,3-dihydrobenzofu -ol
  • Step 5 6-(1 -chloroethyl)-2-methyl-2, 3-dihydrobenzofuran
  • Step 7 1 -(1 -(2-methyl-2,3-dihydro e dihydrochloride
  • Step 2 1, 4-dibromo-2-(3-bromopropyl)
  • Step 4 tert-butyl 4-(1 -(benzo[d]thiazol-5-yl)ethyl)piperazine-1 -carboxylate:
  • the hydrochloride salt was dissolved in water (2.5 L) and aqueous layer was washed with EtOAc (3 x 2 L) and DCM (3 x 2 L). The resulting aqueous layer was basified with 6N NaOH (pH -12) and extracted with EtOAc (3 x 2 L). The combined organic layer was washed with brine (500 ml_), water (500 ml_), dried over anhydrous Na 2 S0 4 and concentrated under vacuum to afford the title compound. Yield: 70% (350 g, pale brown gummy solid).
  • the salt (66 g, 79% ee) was further refluxed in EtOH (1 L, 10V) for 24 h and stirred at RT overnight.
  • EtOH 200 mL, 2V
  • diethyl ether 200 mL
  • dried under high vacuum The same procedure was repeated to achieve the ee of 96.1 % (21.2 g). This step was repeated on 300 g scale to obtain the salt (1 13.2 g).
  • Step 1 (R)-2-chloro-5-(methylsulfinyl)pyrimidine and (S)-2-chloro-5-(methylsulfinyl)pyrimidine :
  • the intermediate 9 (502 g, 2.84 mol) was separated by SFC chromatography (Pic SFC 10-150; C0 2 : IPA (70:30); column: Lux A1 (250 x 30); flow rate: 100 mL/min; wave length: 210 nm; cycle time: 5 min; back pressure: 100 bar, Method E).
  • the first eluting peak (250.0 L of IPA) was concentrated at 40 °C. Yield: 40% (201.0 g, white solid).
  • 1 H NMR 400 MHz, DMSO-c 6 ): ⁇ 9.05 (s, 2H), 2.98 (s, 3H).
  • LCMS (Method A) 177.0 (M+H), Rt. 0.7 min, 99.9% (Max).
  • Chiral SFC (Method E) Rt 2.1 min, 100% (Max).
  • Step 2 N-((2-chloropyrimidin-5-yl)-(S)-(methyl)(oxo)-A -sulfanylidene)-2,2,2-trifluoroacetamide and N-((2-chloropyrimidin-5-yl)-(R)-(methyl)(oxo)-A 6 -sulfanylidene)-2,2,2-trifluoroa
  • step 1 To the stirred solution of the first eluting compound isolated in step 1 (0.5 g, 2.8 mmol) in DCM (5 ml_), trifluroacetamide (0.64 g, 5.66 mmol), MgO (0.45 g, 1 1.3 mmol), Rh 2 (OAc) 4 (0.062 g, 0.14 mmol) and Phl(OAc) 2 (1.36 g, 4.20 mmol) were added and the reaction mixture was stirred at RT overnight. Completion of the reaction was monitored by TLC. The reaction mixture was then filtered through celite, washed with DCM.
  • Step 1 2-chloro-5-(ethylthio)pyrimidine
  • f-butyl nitrite 5.99 g, 58.13 mmol
  • 2-diethyldisulfane 9.4 g, 77.51 mmol
  • DCM 200 mL
  • 2-chloropyrimidin-5-amine 5 g, 38.75 mmol
  • Step 3 N-((2-chloropyrimidin-5-yl) (e e)-2, 2, 2-trifluoroacetamide
  • Step- 1 2-chloro-5-(propylthio)pyrimidine
  • Step-2 2-chloro-5-(propylsulfinyl)pyrimidine
  • Step-3 N-((2-chloropyrimidin-5-yl)(oxo) e)-2, 2, 2-trifluoroacetamide
  • Step 3 N-((6-chloropyridin-3-yl)(methyl) xo)-A 6 -sulfanylidene)-2,2,2-trifluoroacetam
  • Step 3 N-(( 6-chloropyridin-3-yl) (ethyl) -2, 2, 2-trifluoroacetamide
  • Step 1 methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate
  • Step 2 methyl 2-(4-(A 2 -chloranyl)-4A 4 -piperazin-1-yl)pyrimidine-5-carboxylate
  • Step 1 tert-butyl 4-(4-(methylthio)phe te
  • Step 3 1 -(quinolin-7-yl)ethan-1 -ol
  • methyl magnesium chloride 5.4 g, 16.20 mmol
  • TLC THF
  • sat NH 4 CI 15 mL
  • DCM DCM
  • Step 1 tert-butyl 4-carbamimidoylpiperazin -1-carboxylate
  • Step 3 tert-butyl 4-(7, 8-dihydro-5H-th -2-yl)piperazine-1-carboxylate
  • Step 4 tert-butyl 4-(6-oxido-7, 8-dihydro-5H-thiopyrano[4, 3-d]pyrimidin-2-yl)piperazine- 1 - carboxylate
  • Step 5 tert-butyl 4-(6-imino-6-oxido-5,6, 7,8-tetrahydro-6l4-thiopyrano[4,3-d]pyrimidin-2- yl)piperazine-1-carboxylate
  • Step 2 1 -(quinoxalin-6-yl)ethan-1 -ol
  • Step 4 tert-butyl 4-(1 -(quinoxalin-6-yl) ethyl) piperazine-1 -carboxylate
  • Step 5 6-(1-(piperazin-1-yl) ethyl) quinoxaline hydrochloride
  • Step 4 (R)-1, 4-dibromo-2-((1-bromop e
  • Step 7 (2R)-6-(1-chloroethyl)-2-methyl-2, 3-dihydrobenzofuran
  • 1-((R)-2-methyl-2, 3-dihydrobenzofuran-6-yl)ethan-1-ol 0.5 g, 2.80 mmol
  • SOCI 2 (0.48 mL, 4.79 mmol) was added 0 °C and the reaction mixture was stirred at RT for 1 h. After completion (monitored by TLC), the reaction mixture was concentrated under vacuum and the resulting crude material was co-distilled with dry DCM (2 x 500 mL) to afford the title compound. Yield: 98% (crude, 500 mg, brown gummy oil).
  • Step 8 tert-butyl 4-(1 -((R)-2-meth -2, 3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate
  • Step 9 1-(1-((R)-2-methyl-2, razine dihydrochloride
  • Example 1 (2-(4-(1-(2, 3-dihvdrobenzofuran-6-yl)ethyl)piperazin-1 -yl)pyrimidin-5- yl)(imino)(methyl) ⁇ 6 -sulfanon
  • Step 2 (2-(4-( 1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)(imino)(m sulfanone
  • Example 3 (2-(4-(1 -(2, 3-dihvdrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5- yl)(ethyl)(imino) ⁇ 6 -sulfanone
  • Example 7 (6-(4-(1 -(2,3-dihvdrobenzofuran-6-yl)ethyl)piperazin-1 -yl)pyridin-3- yl)(imino)(methyl)-A 6 -sulfanone
  • Example 8 (2-(4-(1 -(2,3-dihvdrobenzofuran-6-yl)ethyl)piperazin-1 -yl)pyrimidin-5- yl)(methyl)(methylimino) ⁇ 6 -sulfanone
  • Example 1 To a stirred solution of Example 1 (0.1 g, 0.25 mmol) in THF (1.0 ml_, 10V), NaH (60%) (16 mg, 0.63 mmol) was added at 0 °C and the resulting mixture was stirred for 15 min at this temperature. Mel (0.048 ml_, 0.75 mmol) was added and the reaction mixture was stirred at RT overnight in a sealed tube. Completion of the reaction was monitored by TLC, then the reaction mixture was concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 1-3% methanol in DCM) to afford the title compound. Yield: 19% (29 mg, off white solid).
  • Step 1 5-bromo-2-(4-( 1-(2, 3 1 -yl)pyrimidine:
  • Example 11 (4-(4-(1 -(2,3-dihvdrobenzofuran-6-yl)ethyl)piperazin-1 -yl)phenyl)(imino)(methyl)- ⁇ ⁇ - ⁇
  • Step 1 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-4-(4-(methylthio)phenyl)piperazine
  • TEA (2.76 ml_, 19.67 mmol)
  • 6-(1-chloroethyl)-2,3-dihydrobenzofuran (synthesis described in intermediate 1 , Steps 1 to 5) (1.197 g, 6.557 mmol) were added at RT and stirred overnight at 70 °C. Completion of the reaction was monitored by TLC, then the reaction mixture was evaporated at 50 °C under reduced pressure.
  • Step 3 (4-(4-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)phenyl)(imino)(methyl)-A 6 - sulfanone
  • Example 16 (2-(4-((S)-1 -(2,3-dihvdrobenzofuran-6-yl)ethyl)piperazin-1 -yl)pyrimidin-5- yl)(imino)(methyl) ⁇ 6 -sulfanone or (2-(4-((R)-1-(2,3-dihvdrobenzofuran-6-yl)ethyl)piperazin-1 - vn P yrimidi -5-vn(imino)(methvn-/ ' -sulfanone
  • Example 18 (S)-(2-(4-((S)-1 -(2,3-dihvdrobenzofuran-6-yl)ethyl)piperazin-1 -yl)pyrimidin-5- yl)(ethylimino)(methyl) ⁇ 6 -sulfanone or (R)-(2-(4-((S)-1 -(2,3-dihydrobenzofuran-6- yl)ethyl)piperazin-1 -yl)pyrimidin-5-yl)(ethylimino)(methyl) ⁇ 6 -sulfanone or (S)-(2-(4-((R)-1 -
  • Example 19 (S)-(2-(4-((S)-1 -(2, 3-dihvdrobenzofuran-6-yl)ethyl)piperazin-1 -yl)pyrimidin-5- yl)(isopropylimino)(methyl) ⁇ 6 -sulfanone or (R)-(2-(4-((S)-1 -(2, 3-dihydrobenzofuran-6- yl)ethyl)piperazin-1 -yl)pyrimidin-5-yl)(isopropylimino)(methyl) ⁇ 6 -sulfanone or (S)-(2-(4-((R)- 1 -(2, 3-dihvdrobenzofuran-6-yl)ethyl)piperazin-1 -yl)pyrimidin-5-yl)(isopropylimino)(methyl)- ⁇ 6 - ⁇ 3 ⁇ 6 or (RH2-(4-((R)-1 -12, 3-dihydro
  • the resulting crude mixture was purified by flash chromatography (Biotage Isolera, gradient: 5% methanol in DCM). The obtained material was further purified by preparative HPLC (Method B). The resulting TFA salt was dissolved in DCM (10 mL) and NaHC0 3 (100 mg) was added. The DCM layer was stirred for 30 min, filtered through celite. The filtrate was evaporated at 45 °C under reduced pressure to afford the title compound. Yield: 36% (58 mg, white solid).
  • Example 20j (6-(4-((S)-1 -(2,3-dihvdrobenzofuran-6-yl)ethyl)piperazin-1 -yl)pyridin-3- yl)(methyl)(methylimino) ⁇ 6 -sulfanone or (6-(4-((R)-1-(2,3-dihydrobenzofuran-6- vnethvn P i P erazin-1 -vn P yridin-3-vn(methvn(methylimino)-/ ' -sulfanone
  • Step 1 N-((6-(4-((S)- 1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazin- 1 -yl)pyridin-3-yl) (methyl) (oxo)- A 6 -sulfanylidene)-2,2,2-trifluoroacetamide or N-((6-(4-((R)-1-(2, 3-dihydrobenzofuran-6- yl)ethyl)piperazin- 1 -yl)pyridin-3-yl)(methyl) (oxo)- A 6 -sulfanylidene)-2, 2, 2-trifluoroacetamide
  • Step 2 (6-(4-((S)-1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)(im
  • step 1 To a stirred solution of the product obtained in step 1 (550 mg, 1.14 mmol) in EtOH (10 mL), K 2 C0 3 (354 mg, 2.28 mmol) was added and stirred at RT for 2h. Completion of the reaction was monitored by TLC, then the reaction mixture was evaporated under vacuum. To the resulting mixture, water (10 mL) was added and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the title compound. Yield: 90% (400 mg, off white solid).
  • Step 3 (6-(4-((S)-1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yO yl)(methyl)(methylimino)-A 6 -sulfanone or (6-(4-((R)-1 -(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1 - yl)pyridin-3-yl) (methyl) (methylimino)-A 6 -sulfanone
  • NaH 60%)
  • Example 21 (2-(4-(1 -(chroman-7-yl)ethyl)piperazin-1 -yl)pyrimidin-5-yl)(imino)(methyl) ⁇ 6 - sulfanone
  • Example 25j (2-(4-(1 -(benzord1thiazol-5-yl)ethyl)piperazin-1 -yl)pyrimidin-5- yl)(methyl)(methylimino) ⁇ 6 -sulfanone
  • Example 22 To a stirred solution of example 22 (0.1 g, 0.25 mmol) in THF (1.0 ml_, 10V), NaH (60%) (18 mg, 0.37 mmol) was added at 0 °C and stirred for 15 min. Then Mel (0.04 ml_, 0.62 mmol) was added to the reaction mixture in a sealed tube and heated overnight at 90 °C. Completion of the reaction was monitored by TLC, then the reaction mixture was concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 5-6% methanol in DCM) and further purified by Prep.HPLC (Method B) to afford the title compound. Yield: 23% (23 mg, off white solid).
  • Example 28 (2-(4-(1 -(benzord1thiazol-5-yl)ethyl)piperazin-1 -yl)pyrimidin-5- yl)(isopropylimino)(methyl) ⁇ 6 -sulfanone
  • Step 1 5-(1-(4-(5-bromopyrimidin- -yl)piperazin-1-yl)ethyl)benzo[d]thiazole
  • Step 1 ethyl 2-(4-(1-(benz e-5-carboxylate
  • Step 2 2-(4-(1 ⁇ enzo[d]thiazol- -yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylic acid
  • Step 1 5-(1-(4-(4-(methylthio)ph iazole
  • Step 2 5-(1-(4-(4-(methylsulfinyl) zole
  • Step 3 (4-(4-(1-(benzo[d]thiazol- -yl)ethyl)piperazin-1-yl)phenyl)(imino)(m
  • Example 34 (2-(4-((S)-1-(benzord1thiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5- yl)(imino)(methyl) ⁇ 6 -sulfanone or (2-(4-((R)-1 -(benzord1thiazol-5-yl)ethyl)piperazin-1 - yl)pyrimidin-5-yl)(imino)(methyl) ⁇ 6 -sulfanone

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Abstract

La présente invention concerne des composés de formule (I) dans laquelle A, R, W, Q, n et m ont la signification indiquée dans les revendications, ces composés pouvant être utilisés, entre autres, pour le traitement de tauopathies et de la maladie d'Alzheimer.
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US16/488,139 US11261183B2 (en) 2016-02-25 2017-08-24 Sulfoximine glycosidase inhibitors
AU2017400271A AU2017400271B2 (en) 2017-02-24 2017-08-24 Sulfoximine glycosidase inhibitors
KR1020197027278A KR20190118184A (ko) 2016-02-25 2017-08-24 술폭시민 글리코시다제 억제제
MX2019010085A MX2019010085A (es) 2017-02-24 2017-08-24 Inhibidores de la glicosidasa de sulfoximina.
SG11201907774VA SG11201907774VA (en) 2017-02-24 2017-08-24 Sulfoximine glycosidase inhibitors
EA201991697A EA201991697A1 (ru) 2016-02-25 2017-08-24 Сульфоксиминовые ингибиторы гликозидазы
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BR112019017514-8A BR112019017514A2 (pt) 2016-02-25 2017-08-24 Composto, mistura, métodos para tratar uma tauopatias e para inibir uma glicosidase, e, composição farmacêutica
PCT/EP2017/071385 WO2018153508A2 (fr) 2017-02-24 2017-08-24 Inhibiteurs de la sulfoximine glycosidase
CN201780089984.7A CN110770226B (zh) 2016-02-25 2017-08-24 亚砜亚胺糖苷酶抑制剂
JP2019545961A JP7082446B2 (ja) 2016-02-25 2017-08-24 スルホキシイミングリコシダーゼ阻害剤
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US10556902B2 (en) 2016-02-25 2020-02-11 Asceneuron Sa Glycosidase inhibitors
WO2020039030A1 (fr) * 2018-08-22 2020-02-27 Asceneuron S. A. Sels d'addition d'acide succinate et fumarate de dérivés de pipérazine utiles en tant qu'inhibiteurs de glycosidase
US10696668B2 (en) 2016-02-25 2020-06-30 Asceneuron Sa Acid addition salts of piperazine derivatives
US11213525B2 (en) 2017-08-24 2022-01-04 Asceneuron Sa Linear glycosidase inhibitors
US11612599B2 (en) 2016-02-25 2023-03-28 Asceneuron Sa Glycosidase inhibitors
US11731972B2 (en) 2018-08-22 2023-08-22 Asceneuron Sa Spiro compounds as glycosidase inhibitors
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