Deuterated bicyclic heteroaryl derivatives

Abstract

The invention provides new deuterated bicyclic heteroaryl compounds having the general formula (I), wherein R1, R2, R3, R4 and R5 are as described herein, compositions including the compounds, and methods of using the compounds.

Description

[0001] Case P39401

[0002] DEUTERATED BICYCLIC HETEROARYL DERIVATIVES

[0003] Field of the invention

[0004] The present invention relates to deuterated bicyclic heteroaryl compounds useful as gamma-secretase modulators, their manufacture, pharmaceutical compositions comprising said compounds and their use as medicaments for the therapeutic and / or prophylactic treatment of diseases associated with the deposition of P-amyloid in the brain, such as Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, amyloid- mediated brain disorders caused by head injuries e.g. chronic traumatic encephalopathy and amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

[0005] Background of the invention

[0006] Alzheimer’s disease (AD) is the most common cause of dementia in later life. Pathologically, AD is characterized by the deposition of amyloid in extracellular plaques and intracellular neurofibrillary tangles in the brain. The amyloid plaques are mainly composed of amyloid peptides (Ap peptides) which originate from the P-Amyloid Precursor Protein (APP) by a series of proteolytic cleavage steps. Several forms of APP have been identified of which the most abundant are proteins of 695, 751 and 770 amino acids length. They all arise from a single gene through differential splicing. The Ap peptides are derived from the same domain of the APP.

[0007] Ap peptides are produced from APP through the sequential action of two proteolytic enzymes termed P- and y-secretase. P-Secretase cleaves first in the extracellular domain of APP just outside of the trans-membrane domain (TM) to produce a C-terminal fragment of APP (CTF0) containing the TM- and cytoplasmatic domain. CTF0 is the substrate for y- secretase which cleaves at several adjacent positions within the TM to produce the A0 peptides and the cytoplasmic fragment. Various proteolytic cleavages mediated by y-secretase result in Ap peptides of different chain lengths, e.g. AP38, Ap40 and Ap42. The latter one is regarded to be the more pathogenic amyloid peptide because of its strong tendency to form neurotoxic aggregates. P-Secretase is a typical aspartyl protease. y-Secretase is a high molecular weight complex that consists of four essential subunits: presenilin (PS, including PSI and PS2), nicastrin, anterior pharynx defective 1 (APH-1), and presenilin enhancer 2 (PEN-2). The atomic structure of human y-secretase at 3.4 A resolution has been published (X. Bai, C. Yan, G. Yang, P. Lu, D. Ma, L. Sun, R. Zhou, S. H. W. Scheres, Y. Shi, Nature, 525 (2015), 212 - 217). The presenilins are bearing the catalytic site and represent a group of atypical aspartyl proteases which cleave their substrates within the TM and which are themselves polytopic membrane proteins. The other essential components of y-secretase, nicastrin and the products of the aphl and pen -2 genes are believed to be responsible for substrate recognition and recruitment. Proven substrates for y-secretase are APP and the proteins of the Notch receptor family, however, y-secretase has a loose substrate specificity and many further membrane proteins unrelated to APP and Notch have been reported to be cleaved by the y-secretase in vitro.

[0008] The y-secretase activity is absolutely required for the production of Ap peptides. This has been shown both by genetic means, i.e. ablation of the presenilin genes, and by low- molecular weight inhibitory compounds. According to the amyloid cascade hypothesis for AD the production and deposition of Ap is the ultimate cause for the disease. Therefore, it is believed that selective and potent inhibition of y-secretase might be useful for the prevention and treatment of AD.

[0009] An alternative mode of treatment is the modulation of the y-secretase activity which results in a selective reduction of the Ap42 production. This would lead to an increase of shorter Ap isoforms, such as Ap38, Ap37 or others, which have no or reduced capability for aggregation and plaque formation, and are not or less neurotoxic. Compounds modulating y- secretase activity include certain non-steroidal anti-inflammatory drugs (NSAIDs) and related analogues (Weggen et al., Nature, 414 (2001) 212-216). Numerous documents describe the current knowledge on y-secretase modulation, such as the following publications: Morihara et aL, J. Neurochem., 83 (2002), 1009-12; Jantzen et aL, J. Neuroscience, 22 (2002), 226-54; Takahashi et al., J. Biol. Chem., 278 (2003), 18644- 70 ; Beher et al., J. Biol. Chem., 279 (2004), 43419-26; Lleo et al., Nature Med., 10 (2004), 1065-6; Kukar et al., Nature Med., 11 (2005), 545-50; Perretto et al., J. Med. Chem., 48 (2005), 5705-20; Clarke et al., J. Biol. Chem., 281 (2006) 31279-89; Stock et al., Bioorg. Med. Chem. Lett., 16 (2006) 2219-2223; Narlawar et al., J. Med. Chem., 49 (2006) 7588-91; Ebke et al., J. Biol. Chem., 286 (2011) 37181-86; Oehlich, Gijsen et al., J. Med. Chem., 54 (2011), 669 - 698; Li et al., Biochemistry, 52 (2013), 3197 - 3216; Hall et al., Progress in Med. Chem., 53 (2014) 101-145; Bursavich et al., J. Med. Chem., 59 (2016); WO 2018 / 111926.

[0010] WO 2020 / 120521 discloses 7-phenoxy-N-(3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine derivatives and related compounds as gamma-secretase modulators useful for the treatment of Alzheimer's disease.

[0011] Therefore, modulating the y-secretase activity is a promising therapeutic strategy for the treatment or prevention of diseases associated with the deposition of P-amyloid in the brain, such as Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, amyloid-mediated brain disorders caused by head injuries e.g. chronic traumatic encephalopathy and amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

[0012] There is a need for new compounds, formulations, treatments and therapies to treat diseases and disorders associated with the deposition of P-amyloid in the brain. It is, therefore, an object of this invention to provide compounds useful for the treatment or prevention or amelioration of such diseases and disorders with improved therapeutic properties, in particular improved cardiac safety. of the invention

[0013] A first object of the present invention is a compound of formula (I) wherein

[0014] R1, R2and R3each independently are hydrogen or deuterium,

[0015] R4is hydrogen or deuterium,

[0016] R5is hydrogen or deuterium; with the proviso that at least one of R1, R2, R3, R4and R5is deuterium; or a pharmaceutically acceptable salt thereof.

[0017] A further object of the invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.

[0018] A further object of the invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0019] A further object of the invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

[0020] A further object of the invention is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

[0021] A further object of the invention is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA- D), multi-infarct dementia, dementia pugilistica, chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

[0022] A further object of the invention is a method for the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome, which method comprises administering an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0023] Detailed description of the invention

[0024] The following definitions of the general terms used in the present description apply irrespectively of whether the terms in question appear alone or in combination with other groups.

[0025] The term “allosteric modulator” denotes a compound that binds to a receptor at a site distinct from the active site. It induces a conformational change in the receptor, which alters the affinity of the receptor for the endogenous ligand. Positive allosteric modulators increase the affinity, whilst negative allosteric modulators decrease the affinity. The terms “asymmetric carbon atom” and “asymmetric center” mean a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom can be of the “R” or “S” configuration.

[0026] The term “half maximal inhibitory concentration” (IC50) denotes the concentration of a particular compound required for obtaining 50% inhibition of a biological process in vitro. IC50 values can be converted logarithmically to pIC50 values (-log IC50), in which higher values indicate exponentially greater potency. The IC50 value is not an absolute value but depends on experimental conditions e.g. concentrations employed. The IC50 value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099).

[0027] The term “hERG” denotes the human ether-a-go-go related gene. It encodes the inward rectifying voltage gated potassium channel in the heart (IKr) which is involved in cardiac repolarization. Inhibition of the hERG current by drugs or by rare mutations may cause QT interval prolongation resulting in potentially fatal ventricular tachyarrhythmia called “Torsades de Pointes”.

[0028] A number of clinically successful drugs in the market have had the tendency to inhibit hERG, lengthening the QT and potentially leading to a fatal irregularity of the heartbeat (a ventricular tachyarrhythmia called torsades de pointes). This has made hERG inhibition an important antitarget that must be avoided during drug development.

[0029] The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

[0030] The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid.

[0031] The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and poly amine resins.

[0032] The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.

[0033] The term “protecting group” (PG) denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protective groups can be removed at the appropriate point. Exemplary protective groups are amino-protective groups, carboxy -protective groups or hydroxy -protective groups. Particular protective groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Further particular protective groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc). More particular protective group is the tert-butoxycarbonyl (Boc). Exemplary protective groups and their application in organic synthesis are described, for example, in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.

[0034] The term “therapeutically effective amount” denotes an amount of a compound of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.

[0035] The following abbreviations are used in the present text:

[0036] DEA = diethylamine, ee = enantiomeric excess, Et2O = diethylether, EtOAc = ethyl acetate, EtOH = ethanol, FCS = fetal calf serum, GCMS = gas chromatography mass spectrometry, h = hour(s), HPLC = high-performance liquid chromatography, IMDM = Iscove’s modified Dulbecco’s medium, LCMS = liquid chromatography mass spectrometry, MeOH = methanol, MOM = methoxymethyl, min = minute(s), ml = milliliter, pl = microliter, MS = mass spectrum, nBuLi = n-butyllithium, OAc = acetoxy, RT = room temperature, SFC = supercritical fluid chromatography, tBuXPhos = 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, THF = tetrahydrofuran.

[0037] Compounds of the invention

[0038] In a first aspect, the present invention provides a compound of formula (I)

[0039] (I), wherein

[0040] R1, R2and R3each independently are hydrogen or deuterium,

[0041] R4is hydrogen or deuterium,

[0042] R5is hydrogen or deuterium; with the proviso that at least one of R1, R2, R3, R4and R5is deuterium; or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (la):

[0044] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (lb):

[0045] In one embodiment, R1, R2and R3are deuterium.

[0046] In one embodiment, R4is deuterium.

[0047] In one embodiment, R5is deuterium.

[0048] In a further embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from: (7R)-7-(3,5-difluorophenoxy)-N-[(lR,5S,8s)-3-(6-(trideuteriomethoxy) pyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine; (R)-7-(3,5-difluorophenoxy)-N-[(lR,5S, 8s)-3-(5-deuterio-6-methoxy-pyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine; and (7R)-7-deuterio-7-(3,5-difluorophenoxy)- N-[(1R,5S, 8s)-3-(6-methoxypyridazin-4-yl)-3- azabicyclo[3.2.1 ]octan-8-yl] 6,7-dihydro-5H-pyrrolo[ 1 ,2-b] [ 1 ,2,4]triazol-2-amine.

[0049] Processes of manufacturing

[0050] Processes for the manufacture of compounds of formula (I), or pharmaceutically acceptable salts thereof, as described herein are also an object of the present invention.

[0051] The preparation of compounds of formula (I) as described herein may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary.

[0052] If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rd Ed., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxy carbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

[0053] If starting materials or intermediates contain stereogenic centers, compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can, for example, be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically / enantiomerically enriched starting materials and intermediates. Using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0054] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0055] In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.

[0056] If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section. Pharmaceutical and administration

[0057] Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable thereof, and a pharmaceutically acceptable excipient.

[0058] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions). The administration can also be effected topically, e.g. transdermal administration, or in form of eye drops or ear drops.

[0059] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations, such as tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations. Lactose, corn starch or derivatives thereof, talc, stearic acids or salts thereof, and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules.

[0060] Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatin capsules.

[0061] Suitable carriers for the production of solutions and syrups are, for example, water, alcohols, polyols, saccharose, glucose, invert sugar, vegetable oil, etc.

[0062] Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0063] Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0064] Suitable carriers for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

[0065] Medicaments containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula (I) and / or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more pharmaceutically acceptable excipients.

[0066] The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. In the case of topical administration, the formulation can contain 0.001% to 15% by weight of medicament and the required dose, which can be between 0.1 and 25 mg, and can be administered either by single dose per day or per week, or by multiple doses (2 to 4) per day, or by multiple doses per week. It will, however, be clear that the upper or lower limit given herein can be exceeded when this is shown to be indicated.

[0067] The pharmaceutical composition according to the invention may be prepared as follows.

[0068] Preparation of pharmaceutical compositions comprising compounds of the invention

[0069] Tablet Formulation (Wet Granulation) Manufacturing Procedure :

[0070] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[0071] 2. Dry the granules at 50°C.

[0072] 3. Pass the granules through suitable milling equipment.

[0073] 4. Add ingredient 5 and mix for three minutes; compress on a suitable press.

[0074] Capsule Formulation

[0075] Manufacturing Procedure:

[0076] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[0077] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[0078] 3. Fill into a suitable capsule. Indications

[0079] Also an object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable thereof, for use as therapeutically active substance.

[0080] As described above, compounds of formula (I) and their pharmaceutically acceptable salts are useful as gamma-secretase modulators.

[0081] In one aspect, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of neurodegenerative diseases associated with Ap42-amyloidosis.

[0082] In one aspect, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, amyloid-mediated brain disorders caused by head injuries e.g. chronic traumatic encephalopathy and amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

[0083] In one embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable thereof, for use in the therapeutic and / or prophylactic treatment of Alzheimer’s disease.

[0084] In a further aspect, the present invention provides the use of compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of neurodegenerative diseases associated with Ap42-amyloidosis.

[0085] In a further aspect, the present invention provides the use of compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, amyloid-mediated brain disorders caused by head injuries e.g. chronic traumatic encephalopathy and amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

[0086] In one embodiment, the present invention provides the use of compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of Alzheimer’s disease.

[0087] In a further aspect, the present invention provides the use of compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of neurodegenerative diseases associated with Ap42-amyloidosis.

[0088] In a further aspect, the present invention provides the use of compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA- D), multi-infarct dementia, dementia pugilistica, amyloid-mediated brain disorders caused by head injuries e.g. chronic traumatic encephalopathy and amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome..

[0089] In one embodiment, the present invention provides the use of compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of Alzheimer’s disease.

[0090] In a further aspect, the present invention provides a method for the therapeutic and / or prophylactic treatment of neurodegenerative diseases associated with Ap42-amyloidosis which method comprises administering an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0091] In a further aspect, the present invention provides a method for the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, amyloid-mediated brain disorders caused by head injuries e.g. chronic traumatic encephalopathy and amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome., which method comprises administering an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0092] In one embodiment, the present invention provides a method for the therapeutic and / or prophylactic treatment of Alzheimer’s disease which method comprises administering an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0093] The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

[0094] 1) Preparative examples

[0095] Example 1

[0096] (7R)-7-(3,5-difluorophenoxy)-N-[(lR,5S,8s)-3-(6-(trideuteriomethoxy) pyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine

[0097] Under inert conditions (N2), methanol-d4 (1.06 g, 1.2 mL, 29.51 mmol, 5.000 eq) in dry tetrahydrofuran (10 mL) was added over 10 minutes at 0-5°C to a suspension of sodium hydride (60 % dispersion in mineral oil) (790 mg, 19.75 mmol, 3.346 eq) in extra dry tetrahydrofuran (40 mL). The mixture was stirred for 45 minutes at 60°C. Then, N-[(1S,5R, 8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamic acid tert-butyl ester (2 g, 5.9 mmol, 1.0 eq) was added and stirring was continued at 60°C for 6 h. The suspension was allowed to get cold before it was poured into ice-water (200 mL) and stirred for 20 minutes. The mixture was filtered off and washed several times with water (100 mL), CH3CN (0-5°C) (2x5 mL) and finally with Et2O (3x20 mL). The filter cake was dried under vacuum to afford 1.57 g (5.26 mmol, 89% yield) of N-[(lR,5S)-3-[6-(trideuteriomethoxy)pyridazin-4- yl]-3-azabicyclo[3.2.1]octan-8-yl]carbamic acid trideuteriomethyl ester as an off-white solid ([M+H]+, ESI pos: 299.3).

[0098] Step 2

[0099] The solid from step 1 was suspended in a mixture of t-amyl alcohol (60 mL), KOH-pellets (1.95 g, 29.51 mmol, 5.0 eq) and water (4 mL). The mixture was stirred overnight at 85°C. More KOH (3 g, 45.45 mmol, 7.699 eq) was added to advance the reaction that was further stirred for 24 hours at 100°C. After 48 h of stirring, the suspension was allowed to get cold, filtered and the filter cake was washed several times with t-amyl alcohol (20 mL). The solution was evaporated under vacuum. The crude product was purified by silica gel chromatography to yield [(lR,5S,8S)-3-[6-(trideuteriomethoxy)pyridazin-4-yl]-3- azabicyclo[3.2.1]octan-8-yl]amine (300 mg, 16.83% yield) as a white solid (238.2 [M+H]+, ESI pos).

[0100] (7R)-2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole (47.7 mg, 150.9 umol, 1.000 eq) and [(lR,5S,8S)-3-[6-(trideuteriomethoxy)pyridazin-4-yl]-3- azabicyclo[3.2.1]octan-8-yl]amine (41.47 mg, 165.99 umol, 1.100 eq) were combined with 2- methyl-THF (3.18 mL) stirred and degassed with argon for 5-10 min. Sodium tert-butoxide (21.75 mg, 226.35 umol, 1.500 eq), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (5.25 mg, 12.36 umol, 0.082 eq) and tris(dibenzylidenaceton)dipalladium(0) (5.57 mg, 6.08 umol, 0.040 eq) were added and the reaction was stirred at 80°C for 1.5 hour. After cooling the suspension was absorbed on Isolute® HM-N (4-5 g) and evaporated under vacuum. The crude residue was purified by silica gel chromatography to obtain 57 mg, 78.34% as off-white foam with an ee purity of 75% (minor racemization happened during the reaction). After separation using chiral column (7R)-7-(3,5-difluorophenoxy)-N-((lR,5S,8s)-3-(6- (trideuteriomethoxy) pyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine was obtained (40 mg, 56 % yield) as white powder (473.2 [M+H]+, ESI pos.).

[0101] Example 2

[0102] (R)-7-(3,5-difluorophenoxy)-N-[(lR,5S, 8s)-3-(5-deuterio-6-methoxy-pyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine

[0103] Under inert conditions (N2), at an internal temperature of 52-53°C, iodosuccinimide (390.07 mg, 1.73 mmol, 1.100 eq) were added in small portions over 90 min. to a solution of (R)-7- (3,5-difluorophenoxy)-N-((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan- 8-yl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine (740 mg, 1.58 mmol, 1.0 eq) in acetic acid (12.52 g, 11.94 mL, 208.5 mmol, 132.281 eq). Stirring was continued for 75 min. at 52°C. Acetic acid was removed by evaporation under vacuum and the residue was taken up in water (100 mL) and CH2Q2 (60 mL). The bi-layer mixture was adjusted to pH 10- 11 with 10% sodium carbonate solution. The organic layer was extracted and concentrated under vacuum. The crude product was purified by silica gel chromatography to yield 335 mg, 34.3% yield of (R)-7-(3,5-difhiorophenoxy)-N-((lR,5S, 8s)-3-(5-iodo-6-methoxy-pyridazin- 4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine as a light brown foam (596.09 [M+H]+, ESI pos.).

[0104] Step 2

[0105] (R)-7-(3 , 5 -difluorophenoxy)-N-(( 1 R, 5 S, 8 s)-3 -(5 -iodo-6-methoxy-pyridazin-4-yl)-3 - azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine (210 mg, 335.08 umol, 1.000 eq) was dissolved in methanol-d4 (10 mL, 1.000 eq) and triethylamine (42.38 mg, 58.38 uL, 418.85 umol, 1.250 eq) followed by addition of palladium 10% on activated charcoal (25 mg, 1.000 eq). The suspension was evacuated and back-filled with argon for three times, then evacuated and back-filled with deuterium for three times. The mixture was stirred for 1 h room temperature under deuterium-atmosphere (using a D2- balloon.). The catalyst was removed by filtration over a pad of Celite®. The filtrate was concentrated and purified by column chromatography to yield (R)-7-(3,5-difhiorophenoxy)- N-[(1R,5S, 8s)-3-(5-deuterio-6-methoxy-pyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7- dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine (140 mg, 88%) as an off-white powder. (471.3 [M+H]+, ESI pos.).

[0106] Example 3

[0107] (7R)-7-deuterio-7-(3,5-difluorophenoxy)- N-[(1R,5S, 8s)-3-(6-methoxypyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine

[0108] 2-bromo-5,6-dihydropyrrolo[l,2-b][l,2,4]triazol-7-one (500 mg, 2.48 mmol, 1.0 eq) was dissolved in methanol (23.13 mL) and the reaction was cooled to 0 °C with an ice bath. Sodium borodeuteride (317.17 mg, 267.2 uL, 7.43 mmol, 3.0 eq) was added carefully in three portions and the brown reaction solution was stirred at 0°C for 1 h. The reaction was concentrated under reduced pressure to remove methanol and the residue was diluted with water and 1 M HC1. After extraction 340 mg of 2-bromo-7-deuterio-5,6-dihydropyrrolo[l,2- b][l,2,4]triazol-7-ol was obtained as a light brown powder, the crude material was used in the next step without further purification (205.0 [M+H]+, ESI pos.).

[0109] 2-bromo-7-deuterio-5,6-dihydropyrrolo[l,2-b][l,2,4]triazol-7-ol (340 mg, 1.49 mmol, 1.0 eq) was dissolved in acetonitrile (4.87 mL). 4-(trifluoromethyl)benzenesulfonic acid (3,5- difluorophenyl) ester (514.92 mg, 1.52 mmol, 1.02 eq) and cesium carbonate (583.53 mg, 1.79 mmol, 1.2 eq) were added and the suspension was stirred at 45°C for 3.5 h. The reaction was left overnight and it was filtered over a small pad of dicalite, washed with EtOAc and the filtrate concentrated to dryness. The crude material (700 mg of a brown solid) was dissolved in di chloromethane and purified by flash chromatography to afford 2-bromo-7-deuterio-7- (3,5-difluorophenoxy)-5,6-dihydropyrrolo[l,2-b][l,2,4]triazole (230 mg, 47.14%) as a colorless viscous oil (317.0 [M+H]+, ESI pos.).

[0110] Step 3

[0111] 2-bromo-7-deuterio-7-(3,5-difhiorophenoxy)-5,6-dihydropyrrolo[l,2-b][l,2,4]triazole (230 mg, 703.54 umol, 1.000 eq) was dissolved in dry 2-methyl-THF (7.04 mL) and (1S,5R,8S)- [3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]amine (197.81 mg, 844.25 umol, 1.2 eq) was added. The reaction was stirred and degassed with argon for 10 min. Sodium tert- butoxide (202.84 mg, 2.11 mmol, 3.0 eq) and tBuXPhos Pd G4 (31.42 mg, 35.18 umol, 0.050 eq) were added and the reaction was stirred at 60°C for 1 h. The suspension was allowed to cool and filtered over a 10 g Isolute® NH2-Si-flash cartridge. Washed with EtOAc:EtOH 4: 1 (4x20 mL).The filtrate was under vacuum and the crude purified by flash chromatography to afford (7S / R)-7-deuterio-7-(3,5-difluorophenoxy)-N-[(lR,5S,8s)-3-(6-methoxypyridazin-4- yl)-3-azabicyclo[3.2.1]octan-8-yl]6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]amine (165 mg, 48 %) as off-white foam (471.2 [M+H]+, ESI pos.).

[0112] Step 4

[0113] [Rac [7-deuterio-7-(3,5-difluorophenoxy)- N-[(1R,5S, 8s)-3-(6-methoxypyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl] 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]amine (110 mg, 233.79 umol, 1.000 eq) was separated by chiral SFC (Column: chiral NR. 5 pm, 250 x 20 mm with 40% MeOH+O.2% DEA) to provide the desired (7R)-7-deuterio-7-(3,5- difluorophenoxy)-N-[(lR,5S, 8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl] 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]amine 2 together with its corresponding enantiomer 1.

[0114] Table 1 : Peak results

[0115] The deuterated (R) analog 2 was identified by coinjection with the corresponding nondeuterated analog prepared in a chiral manner (column chiral NR (5 uM, 150x 4.6 mm), solvent: 40-60 MeOH base NR as solvent, retention time 5.047 minutes).

[0116] 2) Biological examples

[0117] 2,1) Cellular y-secretase assay

[0118] Assay procedure

[0119] Human neuroglioma H4 cells overexpressing human APP695 with the Swedish double mutation (K595N / M596L) were plated at 30,000 cell s / well / 100 pL in 96-well plates in IMDM containing 10% FCS, 0.2 mg / L Hygromycin B and incubated at 37°C, 5% CO2. 3-4 h post plating, compounds are a diluted in media and 50 pL is added as 1.5-fold concentrate to achieve the final concentration. Compound incubation is performed for 24 h. Final doses typically range from 4 pM down to 0.0013 pM in half-log steps resulting in an eight-point dose response curve.

[0120] Appropriate controls using vehicle only and reference compound were applied to this assay. The final concentration of NfeSO was 0.4%.

[0121] After incubation at 37°C, 5% CO2, the supernatant was subjected to quantification of secreted Ap42 by the means of an AlphaLisa® assay kit (Human Amyloid beta 1-42 Kit, Perkin Elmer Inc.). 20 pL of the cell culture supernatant was transferred to an assay plate. Then 10 pL of a mixture of the AlphaLisa® coupled capture antibody and the biotinylated detection antibody was added and incubated for 3h at RT while softly shaking the assay plate. After a further addition of 20 pL of the Donor beads the assay plate was incubated for 30 min at RT and constant shaking without exposure to direct light. The assay plate was then read on a Paradigm AlphaLisa® Reader using the build-in program with excitation at 680 nm and emission at 570 nm.

[0122] The measured signals were then used to calculate IC50 values for inhibition of Ap42 secretion by nonlinear regression fit analysis using XLfit 5.3 software (from IDBS Ltd).

[0123] Results

[0124] WO 2020 / 120521 discloses reference compound Pl as example 1.

[0125] Pl

[0126] Table 2 below shows the data for all compounds for the inhibition of Ap42 secretion.

[0127] Table 2

[0128] Examples 1, 2 and 3 exhibit Ap42 IC50 values reduced compared to Ap42 IC50 value of example Pl.

[0129] 2,2) hERG screening

[0130] Assay procedure

[0131] The hERG test was performed using the automated patch clamp system SynchroPatch® 384 (Nanion Technologies GmbH, Germany). K+ currents were measured with the patch-voltage- clamp technique in the whole-cell configuration at 35-37°C using the built-in 384 channel amplifier and associated software (PatchControl 384). Currents were low-pass filtered using the analog 3 kHz Bessel filter and the digital 3 kHz Lanczos filter and are digitized at 5 kHz. Series resistance was typically 2-9 MOhm and was compensated by 80%. Cells were held at a resting voltage of -80 mV and they were stimulated by a voltage pattern to activate hERG channels and conduct outward IKhERG current, at a stimulation frequency of 0.1 Hz (6 bpm). After the cells had stabilized for a few minutes and the currents were steady, the amplitude and kinetics of IKhERG were recorded under control conditions (vehicle control) for 3-5 min. Thereafter, the test item was tested at ascending concentrations (usually 2-4 concentrations). In the screening tests usually 1 and 10 pM are applied. Cells were exposed to each test item concentration for 3 min.

[0132] The effects of a compound on hERG K+-currents parameters was evaluated at 2-4 concentrations in at least 4 cells. The reported current amplitudes represent the maximal amplitude of a peak current. The standard IKhERG blocker E-4031 and 0.1% DMSO were tested as positive and negative controls for the IKhERG block within each experiment. The amplitudes of IKhERG were recorded in each concentration of drug and they were compared to the vehicle control values (taken as 100%) to define fractional blocks. Data are expressed as mean±SEM for each drug concentration. Concentration-response curves were fitted by non-linear regression analysis using EworkBook suite (ID Business Solutions Ltd, UK). Data fit is done with the 4 Parameter Logistic Model (fit = (A+(B / (l+((x / C)AD)))), where A=0 and B=100).

[0133] Results

[0134] Table 3 below shows the data for all compounds for the hERG channel inhibition:

[0135] Table 3

[0136] Examples 1, 2 and 3 exhibit IC50 values higher than those of example PL

Claims

Claims1. A compound of formula (I)(I), whereinR1, R2and R3each independently are hydrogen or deuterium,R4is hydrogen or deuterium,R5is hydrogen or deuterium; with the proviso that at least one of R1, R2, R3, R4and R5is deuterium; or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (la):

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (lb):

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1, R2and R3are deuterium.

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R4is deuterium.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R5is deuterium.

7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from: (7R)-7-(3,5-difluorophenoxy)-N-[(lR,5S,8s)-3-(6-(trideuteriomethoxy) pyridazin-4-yl)- 3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine; (R)-7-(3,5-difluorophenoxy)-N-[(lR,5S, 8s)-3-(5-deuterio-6-methoxy-pyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine; and (7R)-7-deuterio-7-(3,5-difluorophenoxy)- N-[(1R,5S, 8s)-3-(6-methoxypyridazin-4-yl)-3- azabicyclo[3.2.1 ]octan-8-yl] 6,7-dihydro-5H-pyrrolo[ 1 ,2-b] [ 1 ,2,4]triazol-2-amine.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of Alzheimer’sdisease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis- Dutch type (HCHWA-D), multi -infarct dementia, dementia pugilistica, chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

11. The use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis- Dutch type (HCHWA-D), multi -infarct dementia, dementia pugilistica, chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome..

12. The use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome..

13. A method for the therapeutic and / or prophylactic treatment of Alzheimer’ s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis- Dutch type (HCHWA-D), multi -infarct dementia, dementia pugilistica, chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome., which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

14. The invention as hereinbefore described.

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