7-phenoxy-n-(3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5h-pyrrolo[1,2-b][1,2,4]triazol-2-amine derivatives and related compounds as gamma-secretase modulators for treatment of alzheimer's disease

Abstract

To provide bicyclic heteroaryl compounds useful as γ-secretase modulators, compositions comprising the compounds, production processes of the compounds, and the compounds for use in medical methods.SOLUTION: The invention provides 7-phenoxy-N-(3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine derivatives and related compounds of the general formula (I) in the figure. An exemplary compound is, e.g., (R)-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.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to bicyclic heteroaryl compounds useful as γ-secretase modulators, their preparation, pharmaceutical compositions containing said compounds, and their use as medicaments for the therapeutic and / or prophylactic treatment of diseases associated with β-amyloid deposition in the brain such as Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), multi-infarct dementia, dementia pugilistica, and Down's Syndrome. [Background technology]

[0002] Alzheimer's disease (AD) is the most common cause of dementia in later life. Pathologically, AD is characterized by the deposition of amyloid into extracellular plaques and intracellular neurofibrillary tangles in the brain. Amyloid plaques are primarily composed of amyloid peptides (Aβ peptides) derived from the β-amyloid precursor protein (APP) by a series of proteolytic cleavage steps. Several forms of APP have been identified, the most abundant of which are 695, 751 and 770 amino acid long proteins. All of these arise from a single gene through differential splicing. The Aβ peptides are derived from the same domain of APP.

[0003] Aβ peptides are produced from APP by the sequential action of two proteolytic enzymes called β- and γ-secretase. β-secretase first cleaves in the extracellular domain of APP, just outside the transmembrane domain (TM), to produce the C-terminal fragment of APP (CTFβ), which contains the TM and cytoplasmic domains. CTFβ is the substrate for γ-secretase, which cleaves at several adjacent positions within the TM to produce Aβ peptides and cytoplasmic fragments. Various proteolytic cleavages mediated by γ-secretase result in Aβ peptides of different chain lengths, e.g., Aβ38, Aβ40, and Aβ42. The latter are considered to be the more pathogenic amyloid peptides due to their increased tendency to form neurotoxic aggregates. β-secretase is a typical aspartyl protease. γ-Secretase is a high molecular weight complex consisting of four essential subunits: presenilins (PS, including PS1 and PS2), nicastrin, anterior pharynx defective 1 (APH-1) and presenilin enhancer 2 (PEN-2). The atomic structure of human γ-secretase at 3.4 Å resolution has been published (X. Bai, C. Yan, G. Yang, P. Lu, D. Ma, L. Sun, R. Zhou, SHW Scheres, Y. Shi, Nature, 525 (2015), 212-217). Presenilins contain the catalytic site and cleave substrates within the TM, and represent a group of atypical aspartyl proteases that are themselves polytopic membrane proteins. The other essential components of γ-secretase, nicastrin, and the products of the aph1 and pen-2 genes, are thought to be responsible for substrate recognition and recruitment. The established substrates of γ-secretase are proteins of the APP and Notch receptor families, however, γ-secretase has loose substrate specificity and many additional membrane proteins unrelated to APP and Notch have been reported to be cleaved by γ-secretase in vitro.

[0004] γ-secretase activity is absolutely necessary for the production of Aβ peptides. This has been shown by both genetic means, i.e., ablation of the presenilin gene, and by low molecular weight inhibitory compounds. According to the amyloid cascade hypothesis of AD, the production and deposition of Aβ is the ultimate cause of the disease. Therefore, it is believed that selective and potent inhibition of γ-secretase may be useful in the prevention and treatment of AD.

[0005] An alternative mode of treatment is the modulation of γ-secretase activity resulting in a selective reduction in Aβ42 production. This would result in an increase in shorter Aβ isoforms such as Aβ38, Aβ37, etc., which have no or reduced ability to aggregate and form plaques, and no or low neurotoxicity. Compounds that modulate γ-secretase activity include certain nonsteroidal anti-inflammatory drugs (NSAIDs) and related analogues (Weggen et al., Nature, 414 (2001) 212-216).

[0006] A number of documents describe the current knowledge on γ-secretase regulation, including 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. 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. 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. al., J.Med.Chem., 59(2016); WO 2018 / 111926.

[0007] Therefore, modulation of γ-secretase activity is a promising therapeutic strategy for the treatment or prevention of β-amyloid deposition in the brain such as Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), multi-infarct dementia, dementia pugilistica, and diseases associated with Down's syndrome.

[0008] There is a need for new compounds, formulations, procedures and therapies for treating diseases and disorders associated with the deposition of β-amyloid in the brain.It is therefore an object of the present invention to provide compounds useful in the treatment or prevention or amelioration of such diseases and disorders that have improved therapeutic properties. Summary of the Invention

[0009] A first object of the present invention is to provide a compound of formula (I): [ka] (In the formula, R 1 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, or lower alkoxy substituted by halogen; When n=2 or 3, R 1 may be different, m is 1, 2 or 3; n is 1, 2 or 3; Ar is as follows: [ka] (In the formula, R 2 is hydrogen, halogen, lower alkyl, lower alkyl substituted with halogen, or lower alkoxy; R 3 is hydrogen or halogen) is a 6-membered heteroaryl group selected from or a pharma- ceutically acceptable salt thereof.

[0010] A further object of the present invention is a process for preparing a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, comprising the steps of: [ka] Amine 8: [ka] (In the formula, Ar, R 1 , n, and m are as defined above. to form a compound of formula (I); and If desired, the resulting compound is converted into a pharma- ceutically acceptable salt thereof. This includes:

[0011] A further object of the present invention is the compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, when prepared according to the above process.

[0012] A further object of the present invention is a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

[0013] A further object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0014] A further object of the present invention is a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for use in the therapeutic and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), multi-infarct dementia, dementia pugilistica, or Down's Syndrome.

[0015] A further object of the present invention is the use of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), multi-infarct dementia, dementia pugilistica, or Down's Syndrome.

[0016] A further object of the present invention is the use of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the curative and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), multi-infarct dementia, dementia pugilistica, or Down's Syndrome.

[0017] A further object of the present invention is a method for the therapeutic and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), Multi-Infarct Dementia, Dementia Pugilistica, or Down's Syndrome, said method comprising the administration of an effective amount of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The following definitions of general terms used herein: This applies regardless of whether the term appears alone or in combination with other groups.

[0019] The term "lower alkyl," alone or in combination with other groups, refers to a saturated straight or branched chain alkyl group having single or multiple branching, the alkyl group generally containing from 1 to 7 carbon atoms ("C 1~7 Particular lower alkyl groups have 1 to 4 carbon atoms ("C 1 -alkyl"). 1~4 -alkyl").

[0020] The term "lower alkyl substituted by halogen" means an alkyl group as defined above in which at least one hydrogen atom has been replaced by a halogen, preferably fluorine, such as, for example, CF3, CHF2, CH2F, CHFCF3, CH2CHF2, CH2CH2F, CH2C(CH3)2CF3, CH2CF2CF3, CH(CF3)2, CH2CF3, (CH2)2CF3, (CH2)3CF3, CH(CH3)CF3, CF2CF3, etc. A preferred group is CF3.

[0021] The term "alkoxy", alone or in combination, means a radical of the formula alkyl-O-, in which the term "alkyl" has the meaning given above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Particular "alkoxy" radicals are methoxy and tert-butyloxy.

[0022] The term "halogen-substituted lower alkoxy" means a lower alkoxy group as defined above in which at least one hydrogen atom has been replaced with a halogen, preferably fluorine.

[0023] The terms "halogen" or "halo", alone or in combination, mean fluorine, chlorine, bromine or iodine, particularly fluorine, chlorine or bromine, more particularly fluorine and chlorine. The term "halo", in combination with another group, means substitution of said group with at least one halogen, particularly 1 to 5 halogens, especially 1 to 4 halogens, i.e. 1, 2, 3 or 4 halogens.

[0024] The term "pharmaceutically acceptable salts" refers to salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. Particularly preferred pharma- ceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

[0025] The term "protecting group" (PG) refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction, in the sense conventionally associated with synthetic chemistry, can be selectively carried out at an otherwise unprotected reactive site. The protecting group can be removed at the appropriate location. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups, or hydroxy-protecting groups. Particular protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further particular protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more particular protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their uses in organic synthesis are described, for example, in "Protective Groups in Organic Chemistry", TW Greene and PGM Hutts, 5th Edition, 2014, John Wiley & Sons, New York.

[0026] The term "asymmetric carbon atom" means a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0027] The following abbreviations are used in the text: Boc = tert-butyloxycarbonyl, CAS RN = Chemical Abstracts Registry Number, DIAD = diisopropyl azodicarboxylate, DMF = dimethylformamide, EtOAc = ethyl acetate, EtOH = ethanol, FCS = fetal bovine serum, GCMS = gas chromatography mass spectrometry, h = hour, Hal = halogen, Hept = heptane, HPLC = high performance liquid chromatography, IMDM = Iscove's modified Dulbecco's medium, LCMS = liquid chromatography mass spectrometry, MeCN = acetonitrile, MeOH = methanol, Me2SO = dimethylsulfoxide (DMSO), MOM = methoxymethyl, min = minute, ml = milliliter, μl = microliter, MS = mass spectrum, NaOMe = sodium methanol, NaO tBu = sodium tert-butyl oxide, nBuLi = n-butyl lithium, NEt3 = triethylamine (TEA), NMP = N-methyl-2-pyrrolidone, OAc = acetonitrile, Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0), p-TsOH = p-toluenesulfonic acid, R = any group, RT = room temperature, SFC = supercritical fluid chromatography, tBuXPhos = 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, TBME = tert-butylmethyl ether, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, THP = tetrahydropyran.

[0028] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, or lower alkoxy substituted by halogen; When n=2 or 3, R 1 may be different, m is 1, 2 or 3; n is 1, 2 or 3; Ar is as follows: [ka] (In the formula, R 2 is hydrogen, halogen, lower alkyl, lower alkyl substituted with halogen, or lower alkoxy; R 3 is hydrogen or halogen) is a 6-membered heteroaryl group selected from or a pharma- ceutically acceptable salt thereof.

[0029] In one embodiment, a compound of formula (Ia): [ka] (In the formula, R 1 , m, n and Ar are as defined above. or a pharma- ceutically acceptable salt thereof.

[0030] In one embodiment, a compound of formula (Ib): [ka] (In the formula, R 1 , m, n and Ar are as defined above. or a pharma- ceutically acceptable salt thereof.

[0031] In one embodiment, R 1 is a halogen.

[0032] In one embodiment, R 1 is fluorine or chlorine.

[0033] In one embodiment, m is 1 or 2.

[0034] In one embodiment, Ar is: [ka] (In the formula, R 2 is lower alkyl or lower alkoxy; R 3 is hydrogen) or a pharma- ceutically acceptable salt thereof.

[0035] In a further embodiment, Ar is: [ka] (In the formula, R 2 is methyl or methoxy, R 3 is hydrogen) or a pharma- ceutically acceptable salt thereof.

[0036] In a further embodiment, R 1 is a halogen, m is 1 or 2; n is 1, 2, or 3; Ar is as follows: [ka] (In the formula, R 2 is lower alkyl or lower alkoxy; R 3 is hydrogen) or a pharmaceutical salt thereof.

[0037] In a further embodiment, R 1 is fluorine or chlorine, m is 1 or 2; n is 1, 2, or 3; Ar is as follows: [ka] (In the formula, R 2 is methyl or methoxy, R 3 is hydrogen)

[0023] Provided is a compound of formula (I) as described herein, or a pharma- ceutically acceptable compound thereof, wherein R is a 6-membered heteroaryl group selected from:

[0038] The compounds of formula (I), or pharma- ceutically acceptable salts thereof, may contain one or more asymmetric centers and may exist in the form of optically pure enantiomers, e.g., mixtures of enantiomers, such as racemates, mixtures of diastereoisomers, racemic diastereoisomers, or racemic mixtures of diastereoisomers.

[0039] In a further embodiment, (R)-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, (S)-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, (R)-7-(3-chloro-5-fluorophenoxy)-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, (S)-7-(3-chloro-5-fluorophenoxy)-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, (R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-9-(4-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (S)-9-(4-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (R)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (S)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

[0023] There is provided a compound of formula (I) as described herein, selected from:

[0040] In a further embodiment, (R)-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, (S)-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, (R)-7-(3-chloro-5-fluorophenoxy)-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, (S)-7-(3-chloro-5-fluorophenoxy)-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, (R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

[0023] There is provided a compound of formula (I) as described herein, selected from:

[0041] Manufacturing Process Processes for the preparation of the compounds of formula (I) or pharma- ceutically acceptable salts thereof described herein are also an object of the present invention.

[0042] The preparation of the compounds of formula (I) described herein can be carried out in sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the description of the following processes have the meanings previously indicated herein, unless otherwise indicated.

[0043] If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (for example as described in "Protective Groups in Organic Chemistry" by TW Greene and PG M Huts, 3rd Edition, 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-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

[0044] When the starting materials or intermediates contain a stereocenter, the compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known to those skilled in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemates can be separated into their antipodes via diastereomeric salts, for example, by crystallization with optically pure acids, or by separating the antipodes by specific chromatographic methods using either chiral adsorbents or chiral eluents. It is also possible to separate starting materials and intermediates containing a stereocenter to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. The use of such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compounds of formula (I) typically results in the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0045] One skilled in the art will recognize that the reaction sequence may be varied depending on the reactivity and nature of the intermediates.

[0046] More specifically, the compounds of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or by similar methods. The appropriate reaction conditions for the individual reaction steps are known to those skilled in the art. For reaction conditions described in the literature that affect the reactions described, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999. The reactions could be easily carried out with or without a solvent. There is no particular restriction regarding the nature of the solvent used, provided that it does not adversely affect the reaction or the reagents involved, and that it is capable of dissolving the reagents at least to some extent. The reactions described can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reactions described at temperatures ranging from -78°C to reflux. The time required for the reaction can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to the sequence shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0047] In cases where starting materials or intermediates are not commercially available or their synthesis has not been described in the literature, they can be prepared by analogy with existing procedures for analogous materials or as outlined in the experimental section.

[0048] In one embodiment, the compound of formula (I) described herein or a pharma- ceutically acceptable salt thereof is compound 7: [ka] Amine 8: [ka] (In the formula, Ar, R 1 , n, and m are as defined herein) to form a compound of formula (I); and If desired, converting the resulting compound into a pharma- ceutically acceptable salt thereof. It can be prepared by a process comprising:

[0049] In one embodiment, the process according to the invention can be carried out in the presence of a catalyst, such as palladium, and optionally in the presence of a ligand, such as 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl.

[0050] In a further embodiment, the process according to the invention may further comprise carrying out a chiral separation to obtain compounds of formula (Ia) and (Ib).

[0051] In one embodiment, R 1 Compounds of formula (I), wherein n, m and Ar are as described herein, and intermediates thereof, may be prepared according to literature procedures and / or analogously as shown, for example, in Schemes 1 and 2, respectively. [ka]

[0052] The preparation of compounds of formula (I) can start with the protection of 3,5-dibromo-1H-1,2,4-triazole 2 with the MOM group to give 3. Regioselective halolithiation with nBuLi followed by the addition of aldehydes as electrophiles containing carbon chains of different lengths (m=1, 2, or 3) gave alcohols 4. Mitsunobu coupling was then carried out using different phenols to give aryl ether derivatives 5. Simultaneous deprotection of the THP-protected primary alcohol and the MOM-protected triazole under acidic conditions gave derivatives 6. Intramolecular cyclization was then carried out using cyanomethylenetrimethylphosphorane to give 7. Finally, Buchwald-type coupling with amines of formula 8 in the presence of palladium and ligands gave compounds of formula (I). Separation of the enantiomers was possible by preparative chiral HPLC. [ka]

[0053] Compound 8, as shown in Scheme 1, can be prepared starting from tert-butyl N-[(1S,5R,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate 9 (CAS RN 847862-26-4) according to Scheme 2. Coupling of 9 with heterocyclic halides of general formula Ar-X can be carried out using a substitution reaction under thermal conditions in solvents such as ethanol or NMP in the presence of a base such as Et3N or under catalytic conditions (e.g., palladium(0) or copper(II) catalyst), to give compound 10. After deprotection with an acid (e.g., trifluoroacetic acid), compound 8 is obtained. Heterocyclic halides are either commercially available or are well known in the literature and can be prepared by methods known in the art.

[0054] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable compound thereof, when prepared according to any one of the processes described herein.

[0055] Pharmaceutical Compositions and Administration Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharma- ceutically acceptable compound thereof, and a pharma- ceutically acceptable excipient.

[0056] The compounds of formula (I) and their pharma- ceutically acceptable salts can be used as medicines in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal drops) or rectally (e.g., in the form of suppositories). However, administration can also be parenterally, such as intramuscularly or intravenously (e.g., in the form of injections). Administration can also be topically, for example, transdermally, or in the form of eye or ear drops.

[0057] The compounds of formula (I) and their pharma- ceutically acceptable salts can be processed with pharma- ceutically inert inorganic or organic carriers for the manufacture of pharmaceutical preparations such as tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injectable solutions or topical preparations, etc. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such carriers, for example, for tablets, coated tablets, sugar-coated tablets and hard gelatin capsules.

[0058] Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, in the case of soft gelatin capsules, no carriers are usually required.

[0059] Suitable carriers for the production of solutions and syrups are, for example, water, alcohols, polyols, saccharose, glucose, invert sugar, vegetable oil and the like.

[0060] Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0061] Suitable carriers for topical ophthalmic formulations are, for example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0062] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0063] Medicaments comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient are also an object of the present invention, as well as the process for their preparation, which comprises bringing one or more compounds of formula (I) and / or a pharma- ceutically acceptable salt thereof, and, if desired, one or more other therapeutically valuable substances, together with one or more pharma- ceutically acceptable excipients, into a galenical dosage form.

[0064] The dosage can vary within a wide range and must of course be adjusted to the individual requirements in each specific case. In general, for oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably 0.5 mg to 4 mg / kg body weight (for example about 300 mg / person), preferably divided into 1 to 3 individual doses which may consist of the same amount, will be appropriate. For topical administration, the preparation may contain 0.001% to 15% by weight of the medicament, and the required dose, which may be between 0.1 and 25 mg, may be administered as a single dose per day, as a single dose per week, as multiple doses per day (2 to 4 times) or as multiple doses per week. However, it is clear that, where this is indicated, the upper or lower limits described herein may be exceeded.

[0065] The pharmaceutical composition according to the present invention can be prepared as follows.

[0066] Preparation of pharmaceutical compositions containing compounds of the invention

[0067] [Table 1]

[0068] Manufacturing procedure: 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through a suitable grinding device. 4. Add ingredient 5, mix for 3 minutes and compress in a suitable press.

[0069] [Table 2]

[0070] Manufacturing procedure: 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules.

[0071] Indications Also an object of the present invention are the compounds of formula (I) as described herein, or a pharma- ceutically acceptable compound thereof, for use as therapeutically active substances.

[0072] As noted above, the compounds of formula (I) and their pharma- ceutically acceptable salts are useful as gamma-secretase modulators.

[0073] In one aspect, the invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for use in the therapeutic and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), multi-infarct dementia, dementia pugilistica, or Down's Syndrome.

[0074] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable compound thereof, for use in the therapeutic and / or prophylactic treatment of Alzheimer's disease.

[0075] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), multi-infarct dementia, dementia pugilistica, or Down's Syndrome.

[0076] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of Alzheimer's disease.

[0077] In a further aspect, the present invention provides the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), multi-infarct dementia, dementia pugilistica, or Down's Syndrome.

[0078] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of Alzheimer's disease.

[0079] In a further aspect, there is provided a method for the therapeutic and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), Multi-Infarct Dementia, Dementia Pugilistica, or Down's Syndrome, said method comprising the administration of an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment, the present invention provides a method for the therapeutic and / or prophylactic treatment of Alzheimer's disease, the method comprising administering an effective amount of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof. EXAMPLES

[0081] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the claims.

[0082] Preparation Examples

[0083] overview Analytical method HPLC (method LCMS_fastgradient) Column: Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2.1x30Mm, 1.8μm Solvent A: Water with 0.01% formic acid; Solvent B: Acetonitrile (MeCN) gradient: [Table 3]

[0084] Preparation of intermediates

[0085] 1.2.1) Type 7 intermediate with m=1 [ka]

[0086] Intermediate 7-1: 2-Bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole [ka]

[0087] Step 1: 3,5-Dibromo-1H-1,2,4-triazole (10 g, 44.1 mmol, Eq:1) was combined with DMF (175 ml) to give a pale yellow solution. Under argon and with stirring, sodium hydride (60% in oil) (2.12 g, 52.9 mmol, Eq:1.2) was added in portions (up to 250 mg) over 45 min at up to 25° C., followed by stirring at room temperature for 1 h. Chloro(methoxy)methane (3.55 g, 3.35 ml, 44.1 mmol, Eq:1) was added dropwise over 20 min at up to 25° C., followed by stirring at room temperature for 2 h under argon. The reaction mixture was poured into ice water (400 ml) and extracted three times with TBME (600 ml). The organic layer was washed with water (300 ml) and then with brine (300 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography (Hept:EtOAc 95:5 to 50:50) to give 3,5-dibromo-1-(methoxymethyl)-1H-1,2,4-triazole as a white solid (10.2 g 85%). MS (ES+) m / z: 272.1 [(M+H) + ].

[0088] Step 2: 3,5-Dibromo-1-(methoxymethyl)-1H-1,2,4-triazole (3 g, 11.1 mmol, Eq: 1) was mixed with THF (27 ml) to give a colorless solution, which was then cooled to -75 °C in a dry ice / acetone bath. 1.6 M N-butyllithium in hexane (7.34 ml, 11.7 mmol, Eq: 1.06) was added dropwise over 20 min. The yellow solution was stirred at -75 °C for 45 min. Next, a solution of 3-((tetrahydro-2H-pyran-2-yl)oxy)propanal (2.1 g, 13.3 mmol, Eq: 1.2) in THF (27 ml) was added dropwise over 30 min, followed by stirring at -75 °C for 45 min. The dry ice / acetone bath was removed and the reaction was allowed to warm to approximately 15° C. over 1 h before being quenched with 60 ml of saturated NH4Cl solution, followed by 45 ml of water and 90 ml of EtOAc. The mixture was stirred for 5 min, the layers were separated and the aqueous layer was back extracted with EtOAc (2×90 ml). The organic layer was washed with brine (60 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 80:20 to 0:100) to give 1-(3-bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol as a colorless oil (3.25 g 83.8%). MS (ES+) m / z: 352.0 [(M+H) + ].

[0089] Step 3: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydrofuran-2H-pyran-2-yl)oxy)propan-1-ol (500 mg, 1.43 mmol, Eq: 1) was combined with extra dry THF (25 ml) to give a colourless solution, and 3,5-difluorophenol (223 mg, 1.71 mmol, Eq: 1.2) and triphenylphosphine (468 mg, 1.78 mmol, Eq: 1.25) were added with stirring under argon in an ice bath. The reaction mixture was cooled with stirring under argon. DIAD (361 mg, 347 μl, 1.78 mmol, Eq: 1.25) was added dropwise over 2-3 min at max +3-5°C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(3,5-difluorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (542 mg, 82%). MS (ES+) (-THP) m / z: 378.1 / 380.1 [(M+H) + ].

[0090] Step 4: 3-Bromo-5-(1-(3,5-difluorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole (535 mg, 1.16 mmol, Eq: 1) was combined with methanol (9 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.56 g, 3.8 ml, 46.3 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (30 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (80 ml). The aqueous layer was back extracted with EtOAc (2 x 50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3,5-difluorophenoxy)propan-1-ol as a white solid (350 mg, 90%). MS (ES+) m / z: 334.0 [(M+H) + ].

[0091] Step 5: 3-(3-Bromo-1H-1,2,4-triazol-5-yl)-3-(3,5-difluorophenoxy)propan-1-ol (350 mg, 1.05 mmol, Eq: 1) was combined with extra dry THF (11 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.62 ml, 1.31 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2 x 60 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole as a colorless oil (255 mg, 77%). MS (ES+) m / z: 315.9 [(M+H) + ].

[0092] Intermediate 7-2: 2-Bromo-7-(3-chloro-5-fluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole [ka]

[0093] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydrofuran-2H-pyran-2-yl)oxy)propan-1-ol (500 mg, 1.43 mmol, Eq: 1, as described herein above), 3-chloro-5-fluorophenol (209 mg, 1.43 mmol, Eq: 1) and triphenylphosphine (468 mg, 1.78 mmol, Eq: 1.25) were combined in extra-dry THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (361 mg, 347 μl, 1.78 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(3-chloro-5-fluorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (605 mg, 88%). GCMS (FI+) m / z: 478.9 [(M+H) + ]

[0094] Step 2: 3-Bromo-5-(1-(3-chloro-5-fluorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole (600 mg, 1.25 mmol, Eq: 1) was combined with methanol (9.5 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.94 g, 4.12 ml, 50.1 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. It was cooled to room temperature, poured into ice water (30 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (80 ml). The aqueous layer was back extracted with EtOAc (2 x 50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3-chloro-5-fluorophenoxy)propan-1-ol as a colorless foam (405 mg, 92%). MS (ES+) m / z: 351.9 [(M+H) + ].

[0095] Step 3: 3-(3-Bromo-1H-1,2,4-triazol-5-yl)-3-(3-chloro-5-fluorophenoxy)propan-1-ol (405 mg, 1.16 mmol, Eq: 1) was combined with extra dry THF (12.5 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.89 ml, 1.44 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2 x 60 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-7-(3-chloro-5-fluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole as a colorless oil (284 mg, 73%). MS (ES+) m / z: 333.9 [(M+H) + ].

[0096] Intermediate 7-3: 2-Bromo-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole [ka]

[0097] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydrofuran-2H-pyran-2-yl)oxy)propan-1-ol (504 mg, 1.44 mmol, Eq: 1, as described herein above), 2,3,4-trifluorophenol (256 mg, 1.73 mmol, Eq: 1.2) and triphenylphosphine (472 mg, 1.8 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (364 mg, 350 μl, 1.8 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-1-(methoxymethyl)-5-(3-((tetrahydro-2H-pyran-2)-yl)oxy)-1-(2,3,4-trifluorophenoxy)propyl)-1H-1,2,4-triazole as a pale yellow oil (632 mg, 91%). GCMS (FI+) m / z: 479.0 [(M+H) + ].

[0098] Step 2: 3-Bromo-1-(methoxymethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy)propyl)-1H-1,2,4-triazole (154 mg, 321 μmol, Eq: 1) was combined with methanol (2.5 ml) to give a colorless solution. With stirring under argon, 37% HCl in water (1.26 g, 1.05 ml, 12.8 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (10 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (30 ml). The aqueous layer was back extracted with EtOAc (2×50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(2,3,4-trifluorophenoxy)propan-1-ol as a colorless viscous oil (106 mg, 93%). MS (ES+) m / z: 353.9 [(M+H) + ].

[0099] Step 3: 3-(3-Bromo-1H-1,2,4-triazol-5-yl)-3-(2,3,4-trifluorophenoxy)propan-1-ol (102 mg, 290 μmol, Eq: 1) was combined with extra-dry THF (3 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (724 μl, 362 μmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (20 ml) and saturated sodium bicarbonate solution (3 ml). The aqueous layer was back-extracted with EtOAc (2×20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole as a colorless oil (70 mg, 72%). MS (ES+) m / z: 333.9 [(M+H) + ].

[0100] Intermediate 7-4: 2-Bromo-7-(4-chlorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole [ka]

[0101] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydrofuran-2H-pyran-2-yl)oxy)propan-1-ol (500 mg, 1.43 mmol, Eq: 1, as described herein above), 4-chlorophenol (220 mg, 1.71 mmol, Eq: 1.2) and triphenylphosphine (468 mg, 1.78 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (361 mg, 347 μl, 1.78 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-1-(methoxymethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy)propyl)-1H-1,2,4-triazole as a colorless oil (520 mg, 79%). MS (ES+) m / z: 462.1 [(M+H) + ].

[0102] Step 2: 3-Bromo-5-(1-(4-chlorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole (517 mg, 1.12 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.42 g, 3.69 ml, 44.9 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (35 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2 x 60 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(4-chlorophenoxy)propan-1-ol as a white foam (335 mg, 89%). MS (ES+) m / z: 331.9 [(M+H) + ].

[0103] Step 3: 3-(3-Bromo-1H-1,2,4-triazol-5-yl)-3-(4-chlorophenoxy)propan-1-ol (323 mg, 971 μmol, Eq: 1) was combined with extra-dry THF (10 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.43 ml, 1.21 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. Cooled to room temperature and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back-extracted with EtOAc (2×50 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-7-(4-chlorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole as a white solid (240 mg, 78%). MS (ES+) m / z: 315.9 [(M+H) + ].

[0104] Intermediate 7-5: 2-Bromo-7-(3-chlorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole [ka]

[0105] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydrofuran-2H-pyran-2-yl)oxy)propan-1-ol (500 mg, 1.43 mmol, Eq: 1, as described herein above), 3-chlorophenol (220 mg, 1.71 mmol, Eq: 1.2) and triphenylphosphine (468 mg, 1.78 mmol, Eq: 1.25) (468 mg, 1.78 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (361 mg, 347 μl, 1.78 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(3-chlorophenoxy)-3-((tetrahydro-2H-pyran)-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (545 mg, 82%). MS (ES+) m / z: 462.1 [(M+H) + ].

[0106] Step 2: 3-Bromo-5-(1-(3-chlorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole (540 mg, 1.17 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.62 g, 3.85 ml, 46.9 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (35 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2 x 60 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3-chlorophenoxy)propan-1-ol as a colorless viscous oil (360 mg, 92%). MS (ES+) m / z: 331.9 [(M+H) + ].

[0107] Step 3: 3-(3-Bromo-1H-1,2,4-triazol-5-yl)-3-(3-chlorophenoxy)propan-1-ol (355 mg, 1.07 mmol, Eq: 1) was combined with extra dry THF (11 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.67 ml, 1.33 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2 x 50 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-7-(3-chlorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole as a colorless oil (249 mg, 74%). MS (ES+) m / z: 315.9 [(M+H) + ].

[0108] Intermediate 7-6: 2-Bromo-7-(3,5-dichlorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole [ka]

[0109] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydrofuran-2H-pyran-2-yl)oxy)propan-1-ol (500 mg, 1.43 mmol, Eq: 1, as described herein above), 3,5-dichlorophenol (279 mg, 1.71 mmol, Eq: 1.2) and triphenylphosphine (468 mg, 1.78 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (361 mg, 347 μl, 1.78 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(3,5-dichlorophenoxy)-3-((tetrahydro-2H)-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (625 mg, 82%). GCMS m / z: 494.0 [(M+H) + ].

[0110] Step 2: 3-Bromo-5-(1-(3,5-dichlorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole (620 mg, 1.25 mmol, Eq: 1) was combined with MeOH (10 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.93 g, 4.11 ml, 50.1 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction was then cooled to room temperature, poured into ice water (35 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2 x 60 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3,5-dichlorophenoxy)propan-1-ol as a white foam (408 mg, 88%). MS (ES+) m / z: 367.9 [(M+H) + ].

[0111] Step 3: 3-(3-Bromo-1H-1,2,4-triazol-5-yl)-3-(3,5-dichlorophenoxy)propan-1-ol (400 mg, 1.09 mmol, Eq: 1) was combined with extra dry THF (11.5 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.72 ml, 1.36 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2 x 50 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-7-(3,5-dichlorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole as a colorless oil (288 mg, 75%). MS (ES+) m / z: 349.9 [(M+H) + ].

[0112] 1.2.2) Type 7 intermediate with m=2 [ka]

[0113] Intermediate 7-7: 2-Bromo-8-(3-chloro-5-fluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka]

[0114] Step 1: 3,5-Dibromo-1-(methoxymethyl)-1H-1,2,4-triazole (4 g, 14.8 mmol, Eq: 1, as described herein above) was combined with THF (36 ml) to give a colorless solution, which was cooled to -75°C in a dry ice / acetone bath. n-Butyllithium (1.6 M in hexanes, 9.78 ml, 15.7 mmol, Eq: 1.06) was added dropwise over 20 minutes. The yellow solution was stirred at -75°C for 45 minutes. Next, a solution of 4-((tetrahydro-2H-pyran-2-yl)oxy)butanal (3.05 g, 17.7 mmol, Eq: 1.2) in THF (36 ml) was added dropwise over 30 minutes, and the mixture was then stirred at -75°C for 45 minutes. The dry ice / acetone bath was removed and the reaction mixture was allowed to warm to approximately 15° C. over 1 h before being quenched with 80 ml of saturated NH4Cl solution, followed by 55 ml of water and 120 ml of EtOAc. The mixture was stirred for 5 min, the layers were separated and the aqueous layer was back extracted with EtOAc (2×120 ml). The organic layer was washed with brine (80 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 80:20 to 0:100) to give 1-(3-bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)butan-1-ol as a colorless oil (3.75 g 69%). MS (ES+) m / z: 364.0 [(M+H) + ].

[0115] Step 2: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydrofuran-2H-pyran-2-yl)oxy)butan-1-ol (500 mg, 1.37 mmol, Eq: 1), 3-chloro-5-fluorophenol (241 mg, 1.65 mmol, Eq: 1.2) and triphenylphosphine (450 mg, 1.72 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(3-chloro-5-fluorophenoxy)-4-((tetrahydro)2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (620 mg, 91%). MS (ES+) m / z: 410.0 (-THP) [(M+H) + ].

[0116] Step 3: 3-Bromo-5-(1-(3-chloro-5-fluorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole (620 mg, 1.26 mmol, Eq: 1) was combined with MeOH (10 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.96 g, 4.13 ml, 50.3 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes followed by stirring at reflux for 1 hour. The reaction mixture was stirred without heating for 30 minutes followed by stirring at reflux for 1 hour. The reaction mixture was then cooled to room temperature, poured into ice water (35 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2 x 70 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(3-chloro-5-fluorophenoxy)butan-1-ol as a colorless viscous oil (435 mg, 94%). MS (ES+) m / z: 365.9 [(M+H) + ].

[0117] Step 4: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(3-chloro-5-fluorophenoxy)butan-1-ol (430 mg, 1.18 mmol, Eq: 1) was combined with extra-dry THF (12 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.95 ml, 1.47 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (70 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was back-extracted with EtOAc (2 x 40 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-8-(3-chloro-5-fluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine as a colorless oil (320 mg, 78%). MS (ES+) m / z: 347.9 [(M+H) + ].

[0118] Intermediate 7-8: 2-Bromo-8-(3,5-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka]

[0119] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydrofuran-2H-pyran-2-yl)oxy)butan-1-ol (550 mg, 1.51 mmol, Eq: 1, as described herein above), 3,5-difluorophenol (196 mg, 1.51 mmol, Eq: 1) and triphenylphosphine (495 mg, 1.89 mmol, Eq: 1.25) were combined in THF (27 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (382 mg, 367 μl, 1.89 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(3,5-difluorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (530 mg, 73%). MS (ES+) m / z: 476.0 [(M+H) + ].

[0120] Step 2: 3-Bromo-5-(1-(3,5-difluorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole (530 mg, 1.11 mmol, Eq: 1) was combined with MeOH (8.5 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.39 g, 3.65 ml, 44.5 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction was then cooled to room temperature, poured into ice water (30 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2 x 70 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(3,5-difluorophenoxy)butan-1-ol as a colorless viscous oil (372 mg, 96%). MS (ES+) m / z: 348.0 [(M+H) + ].

[0121] Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(3,5-difluorophenoxy)butan-1-ol (370 mg, 1.06 mmol, Eq: 1) was combined with extra dry THF (11 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.66 ml, 1.33 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2 x 60 ml). The organic layer was washed with brine (80 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-8-(3,5-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine as a colorless oil (254 mg, 72%). MS (ES+) m / z: 330.0 [(M+H) + ].

[0122] Intermediate 7-9: 2-Bromo-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka]

[0123] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydrofuran-2H-pyran-2-yl)oxy)butan-1-ol (500 mg, 1.37 mmol, Eq: 1, as described herein above), 2,3,4-trifluorophenol (244 mg, 1.65 mmol, Eq: 1.2) and triphenylphosphine (450 mg, 1.72 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-1-(methoxymethyl)-5-(4-((tetrahydro-2H-pyran-2)-yl)oxy)-1-(2,3,4-trifluorophenoxy)butyl)-1H-1,2,4-triazole as a pale yellow oil (575 mg, 84%). MS (ES+) m / z: 412.0 (-THP) [(M+H) + ].

[0124] Step 2: 3-Bromo-1-(methoxymethyl)-5-(4-((tetrahydro-2H-pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy)butyl)-1H-1,2,4-triazole (570 mg, 1.15 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.54 g, 3.79 ml, 46.1 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (30 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2 x 70 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(2,3,4-trifluorophenoxy)butan-1-ol as a colorless viscous oil (400 mg, 94%). MS (ES+) m / z: 366.0 [(M+H) + ].

[0125] Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(2,3,4-trifluorophenoxy)butan-1-ol (395 mg, 1.08 mmol, Eq: 1) was combined with extra-dry THF (11 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.7 ml, 1.35 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (70 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was back-extracted with EtOAc (2 x 40 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 2-bromo-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine as a colorless oil (285 mg, 75%). MS (ES+) m / z: 347.9 [(M+H) + ].

[0126] Intermediate 7-10: 2-Bromo-8-(2,4-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka]

[0127] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydrofuran-2H-pyran-2-yl)oxy)butan-1-ol (495 mg, 1.36 mmol, Eq: 1, as described herein above), 2,4-difluorophenol (212 mg, 1.63 mmol, Eq: 1.2) and triphenylphosphine (450 mg, 1.72 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (344 mg, 330 μl, 1.7 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(2,4-difluorophenoxy)-4-((tetrahydro-2H)-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (549 mg, 84%). MS (ES+) m / z: 392.0 (-THP) [(M+H) + ].

[0128] Step 2: 3-Bromo-5-(1-(2,4-difluorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole (545 mg, 1.14 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.51 g, 3.76 ml, 45.8 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (35 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2 x 60 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(2,4-difluorophenoxy)butan-1-ol as a colorless solid (360 mg, 90%). MS (ES+) m / z: 348.0 [(M+H) + ].

[0129] Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(2,4-difluorophenoxy)butan-1-ol (355 mg, 1.02 mmol, Eq: 1) was combined with extra dry THF (10.5 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.55 ml, 1.27 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2 x 50 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-8-(2,4-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine as a colorless oil (285 mg, 75%). MS (ES+) m / z: 330.0 [(M+H) + ].

[0130] Intermediate 7-11: 2-Bromo-8-(3-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka]

[0131] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydrofuran-2H-pyran-2-yl)oxy)butan-1-ol (500 mg, 1.37 mmol, Eq: 1, as described herein above), 3-chlorophenol (212 mg, 1.65 mmol, Eq: 1.2) and triphenylphosphine (450 mg, 1.72 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(3-chlorophenoxy)-4-((tetrahydro-2H-pyran)-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (560 mg, 85%). MS (ES+) m / z: 474.0 [(M+H) + ].

[0132] Step 2: 3-Bromo-5-(1-(3-chlorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole (555 mg, 1.17 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.61 g, 3.84 ml, 46.8 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (30 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2 x 60 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(3-chlorophenoxy)butan-1-ol as a colorless viscous oil (375 mg, 92%). MS (ES+) m / z: 347.9 [(M+H) + ].

[0133] Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(3-chlorophenoxy)butan-1-ol (370 mg, 1.07 mmol, Eq: 1) was combined with extra-dry THF (11 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.67 ml, 1.33 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back-extracted with EtOAc (2 x 50 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-8-(3-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine as a colorless oil (263 mg, 75%). MS (ES+) m / z: 329.9 [(M+H) + ].

[0134] Intermediate 7-12: 2-Bromo-8-(2-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka]

[0135] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydrofuran-2H-pyran-2-yl)oxy)butan-1-ol (492 mg, 1.35 mmol, Eq: 1, as described herein above), 2-chlorophenol (208 mg, 1.62 mmol, Eq: 1.2) and triphenylphosphine (443 mg, 1.69 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(2-chlorophenoxy)-4-((tetrahydro-2H-pyran)-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (560 mg, 85%). MS (ES+) m / z: 392.0 (-THP) [(M+H) + ].

[0136] Step 2: 3-Bromo-5-(1-(2-chlorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole (560 mg, 1.18 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.65 g, 3.87 ml, 47.2 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. It was cooled to room temperature, poured into ice water (30 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2 x 60 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(2-chlorophenoxy)butan-1-ol as a white solid (362 mg, 88%). MS (ES+) m / z: 347.9 [(M+H) + ].

[0137] Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(2-chlorophenoxy)butan-1-ol (360 mg, 1.04 mmol, Eq: 1) was combined with extra-dry THF (11 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.6 ml, 1.3 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back-extracted with EtOAc (2 x 50 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-8-(2-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine as a white solid (260 mg, 76%). MS (ES+) m / z: 329.9 [(M+H) + ].

[0138] Intermediate 7-13: 2-Bromo-8-(4-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka]

[0139] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydrofuran-2H-pyran-2-yl)oxy)butan-1-ol (500 mg, 1.37 mmol, Eq: 1, as described herein above), 4-chlorophenol (212 mg, 1.65 mmol, Eq: 1.2) and triphenylphosphine (450 mg, 1.72 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(4-chlorophenoxy)-4-((tetrahydro-2H-pyran.-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole (489 mg, 75%) as a colorless oil. MS (ES+) m / z: 474.9 [(M+H) + ].

[0140] Step 2: 3-Bromo-5-(1-(4-chlorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole (485 mg, 1.02 mmol, Eq: 1) was combined with MeOH (8 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.03 g, 3.36 ml, 40.9 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (30 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2 x 70 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(4-chlorophenoxy)butan-1-ol as a colorless viscous oil (320 mg, 90%). MS (ES+) m / z: 347.9 [(M+H) + ].

[0141] Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(4-chlorophenoxy)butan-1-ol (310 mg, 894 μmol, Eq:1) was combined with extra-dry THF (11 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.24 ml, 1.12 mmol, Eq:1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (70 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back-extracted with EtOAc (2×50 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-8-(4-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine as a white solid (182 mg, 61%). MS (ES+) m / z: 329.9 [(M+H) + ].

[0142] Intermediate 7-14: 2-Bromo-8-(3,5-dichlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka]

[0143] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydrofuran-2H-pyran-2-yl)oxy)butan-1-ol (509 mg, 1.4 mmol, Eq: 1, as described herein above), 3,5-dichlorophenol (273 mg, 1.68 mmol, Eq: 1.2) and triphenylphosphine (458 mg, 1.75 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (353 mg, 340 μl, 1.75 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(3,5-dichlorophenoxy)-4-((tetrahydro-2H)-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (670 mg, 94%). GCMS m / z: 423.9 (-THP) [(M+H) + ].

[0144] Step 2: 3-Bromo-5-(1-(3,5-dichlorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole (665 mg, 1.31 mmol, Eq: 1) was combined with MeOH (10 ml) to give a colourless solution. Under argon and with stirring, 37% HCl in water (5.15 g, 4.29 ml, 52.2 mmol, Eq: 40) was added (exothermic). The reaction mixture was stirred without heating for 30 min, followed by reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (40 ml), neutralised with solid sodium bicarbonate and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2 x 80 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(3,5-dichlorophenoxy)butan-1-ol as a white foam (435 mg, 87%). MS (ES+) m / z: 381.9 [(M+H) + ].

[0145] Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(3,5-dichlorophenoxy)butan-1-ol (430 mg, 1.13 mmol, Eq: 1) was combined with extra dry THF (12 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.82 ml, 1.41 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (100 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2 x 50 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-8-(3,5-dichlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine as a white solid (285 mg, 69%). MS (ES+) m / z: 363.9 [(M+H) + ].

[0146] Intermediate 7-15: 2-Bromo-8-(2,3-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka]

[0147] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydrofuran-2H-pyran-2-yl)oxy)butan-1-ol (498 mg, 1.37 mmol, Eq: 1, as described herein above), 2,3-difluorophenol (213 mg, 1.64 mmol, Eq: 1.2) and triphenylphosphine (448 mg, 1.71 mmol, Eq: 1.25) were combined in THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (346 mg, 332 μl, 1.71 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(2,3-difluorophenoxy)-4-((tetrahydro-2H)-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (560 mg, 86%). GCMS m / z: 392.0 (-THP) [(M+H) + ].

[0148] Step 2: 3-Bromo-5-(1-(2,3-difluorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole (555 mg, 1.17 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.59 g, 3.83 ml, 46.6 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (35 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2 x 60 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(2,3-difluorophenoxy)butan-1-ol as a colorless viscous oil (375 mg, 92%). MS (ES+) m / z: 348.0 [(M+H) + ].

[0149] Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(2,3-difluorophenoxy)butan-1-ol (372 mg, 1.07 mmol, Eq: 1) was combined with extra dry THF (11 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.67 ml, 1.34 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2 x 60 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-8-(2,3-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine as a white solid (255 mg, 72%). MS (ES+) m / z: 330.0 [(M+H) + ].

[0150] Intermediate 7-16: 2-Bromo-8-(3,4-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka]

[0151] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydrofuran-2H-pyran-2-yl)oxy)butan-1-ol (500 mg, 1.37 mmol, Eq: 1, as described herein above), 3,4-difluorophenol (214 mg, 1.65 mmol, Eq: 1.2) and triphenylphosphine (450 mg, 1.72 mmol, Eq: 1.25) were combined with THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(3,4-difluorophenoxy)-4-((tetrahydro-2H)-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (550 mg, 84%). MS (ES+) m / z: 392.0 (-THP) [(M+H) + ].

[0152] Step 2: 3-Bromo-5-(1-(3,4-difluorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole (550 mg, 1.15 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.55 g, 3.79 ml, 46.2 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (35 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2 x 70 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(3,4-difluorophenoxy)butan-1-ol as a colorless viscous oil (385 mg, 95%). MS (ES+) m / z: 348.0 [(M+H) + ].

[0153] Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(3,4-difluorophenoxy)butan-1-ol (380 mg, 1.09 mmol, Eq: 1) was combined with extra-dry THF (12 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.73 ml, 1.36 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back-extracted with EtOAc (2 x 60 ml). The organic layer was washed with brine (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 0:100) to give 2-bromo-8-(3,4-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine as a colorless oil (292 mg, 81%). MS (ES+) m / z: 330.0 [(M+H) + ].

[0154] 1.2.3) Type 7 intermediate with m=3 [ka]

[0155] Intermediate 7-17: 2-Bromo-9-(4-fluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine [ka]

[0156] Step 1: 3,5-Dibromo-1-(methoxymethyl)-1H-1,2,4-triazole (10.2 g, 37.7 mmol, Eq: 1, described herein above) was combined with THF (90 ml) to give a colorless solution. The mixture was then cooled to -75°C in a dry ice / acetone bath. 1.6 M n-butyllithium in hexanes (24.9 ml, 39.9 mmol, Eq: 1.06) was added dropwise over 20 minutes. The yellow solution was stirred at -75°C for 45 minutes. A solution of 5-((tetrahydro-2H-pyran-2-yl)oxy)pentanal (8.41 g, 45.2 mmol, Eq: 1.2) in THF (90 ml) was then added dropwise over 30 minutes. The mixture was then stirred at -75°C for 45 minutes. The dry ice / acetone bath was removed and the reaction mixture was allowed to warm to approximately 15°C over 1 hour. The reaction mixture was quenched with 190 ml of saturated NH4Cl solution, followed by 190 ml of water and 250 ml of EtOAc. The mixture was stirred for 5 min, the layers were separated, and the aqueous layer was back-extracted with EtOAc (2 x 250 ml). The organic layer was washed with brine (200 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 80:20 to 20:80) to give 1-(3-bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5-((tetrahydro-2H-pyran-2-yl)oxy)pentan-1-ol as a pale yellow oil (11.4 g 80%). MS (ES+) m / z: 378.1 / 380.1 [(M+H) + ].

[0157] Step 2: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5-((tetrahydro-2H-pyran-2-yl)oxy)pentan-1-ol (500 mg, 1.32 mmol, Eq: 1), 4-fluorophenol (178 mg, 1.59 mmol, Eq: 1.2) and triphenylphosphine (433 mg, 1.65 mmol, Eq: 1.25) were combined with THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (334 mg, 321 μl, 1.65 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(4-fluorophenoxy)-5-((tetrahydro-2H-pyran))-2-yl)oxy)pentyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a pale yellow oil (485 mg, 77%). MS (ES+) m / z: 474.1 [(M+H) + ].

[0158] Step 3: 3-Bromo-5-(1-(4-fluorophenoxy)-5-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)-1-(methoxymethyl)-1H-1,2,4-triazole (480 mg, 1.02 mmol, Eq: 1) was combined with MeOH (8 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.01 g, 3.34 ml, 40.6 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (30 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2 x 70 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 90:10 to 0:100) to give 5-(3-bromo-1H-1,2,4-triazol-5-yl)-5-(4-fluorophenoxy)pentan-1-ol (325 mg, 944 μmol, Eq:1) as a colorless viscous oil (330 mg, 94%). MS (ES+) m / z: 346.0 [(M+H) + ].

[0159] Step 4: 5-(3-Bromo-1H-1,2,4-triazol-5-yl)-5-(4-fluorophenoxy)pentan-1-ol (325 mg, 944 μmol, Eq: 1) was combined with extra-dry THF (10 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.36 ml, 1.18 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (60 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was back-extracted with EtOAc (2×40 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 2-bromo-9-(4-fluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine as a colorless viscous oil (308 mg, 58%). MS (ES+) m / z: 326.0 [(M+H) + ].

[0160] Intermediate 7-18: 2-Bromo-9-(2,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine [ka]

[0161] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5-((tetrahydro-2H-pyran-2-yl)oxy)pentan-1-ol (500 mg, 1.32 mmol, Eq: 1, as described herein above), 2,3,4-trifluorophenol (235 mg, 1.59 mmol, Eq: 1.2) and triphenylphosphine (433 mg, 1.65 mmol, Eq: 1.25) were combined with THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (334 mg, 321 μl, 1.65 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-1-(methoxymethyl)-5-(5-((tetrahydro-2H-pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy)pentyl)-1H-1,2,4-triazole as a pale yellow oil (555 mg, 82%). MS (ES+) m / z: 508.1 [(M+H) + ].

[0162] Step 2: 3-Bromo-1-(methoxymethyl)-5-(5-((tetrahydro-2H-pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy)pentyl)-1H-1,2,4-triazole (550 mg, 1.08 mmol, Eq: 1) was combined with MeOH (8 ml) to give a colourless solution. Under argon and with stirring, 37% HCl in water (4.26 g, 3.55 ml, 43.3 mmol, Eq: 40) was added (exothermic). The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. The reaction was then cooled to room temperature, poured into ice water (30 ml), neutralised with solid sodium bicarbonate and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2 x 70 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 80:20 to 0:100) to give 5-(3-bromo-1H-1,2,4-triazol-5-yl)-5-(2,3,4-trifluorophenoxy)pentan-1-ol as a colorless oil (390 mg, 94%). MS (ES+) m / z: 380.0 [(M+H) + ].

[0163] Step 3: 5-(3-Bromo-1H-1,2,4-triazol-5-yl)-5-(2,3,4-trifluorophenoxy)pentan-1-ol (385 mg, 1.01 mmol, Eq: 1) was combined with extra-dry THF (10 ml) to give a colorless solution. Under argon, with stirring, a solution of cyanomethylenetrimethylphosphorane (2.53 ml, 1.27 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (60 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was back-extracted with EtOAc (2 x 40 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 2-bromo-9-(2,3,4-fluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine as a white solid (225 mg, 61%). MS (ES+) m / z: 362.0 [(M+H) + ].

[0164] Intermediate 7-19: 2-Bromo-9-(3-chloro-5-fluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine [ka]

[0165] Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5-((tetrahydro-2H-pyran-2-yl)oxy)pentan-1-ol (500 mg, 1.32 mmol, Eq: 1, as described herein above), 3-chloro-5-fluorophenol (232 mg, 1.59 mmol, Eq: 1.2) and triphenylphosphine (433 mg, 1.65 mmol, Eq: 1.25) were combined with THF (25 ml) to give a colourless solution. The reaction mixture was cooled in an ice bath under argon with stirring. DIAD (334 mg, 321 μl, 1.65 mmol, Eq: 1.25) was added dropwise over 5 min at max +3° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 3-bromo-5-(1-(3-chloro-5-fluorophenoxy)-5-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (565 mg, 84%). MS (ES+) m / z: 506.0 [(M+H) + ].

[0166] Step 2: 3-Bromo-5-(1-(3-chloro-5-fluorophenoxy)-5-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)-1-(methoxymethyl)-1H-1,2,4-triazole (560 mg, 1.1 mmol, Eq: 1) was combined with MeOH (8 ml) to give a colorless solution. Under argon, with stirring, 37% HCl in water (4.36 g, 3.63 ml, 44.2 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 min, followed by stirring at reflux for 1 h. It was cooled to room temperature, poured into ice water (30 ml), neutralized with solid sodium bicarbonate, and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2 x 70 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 80:20 to 0:100) to give 5-(3-bromo-1H-1,2,4-triazol-5-yl)-5-(3-chloro-5-fluorophenoxy)pentan-1-ol as a colorless viscous oil (350 mg, 83%). MS (ES+) m / z: 379.9 [(M+H) + ].

[0167] Step 3: 5-(3-Bromo-1H-1,2,4-triazol-5-yl)-5-(3-chloro-5-fluorophenoxy)pentan-1-ol (380 mg, 1 mmol, Eq: 1) was combined with extra dry THF (10 ml) to give a colorless solution. Under argon and with stirring, a solution of cyanomethylenetrimethylphosphorane (2.51 ml, 1.25 mmol, Eq: 1.25) in THF (0.5 M) was added dropwise over 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc (60 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was back extracted with EtOAc (2 x 40 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (Hept:EtOAc 95:5 to 50:50) to give 2-bromo-9-(3-chloro-5-fluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine as a colorless oil (218 mg, 60%). MS (ES+) m / z: 361.9 [(M+H) + ].

[0168] 1.2.4) Type 8 intermediates

[0169] Intermediate 8-1: (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine [ka]

[0170] Step 1: In a sealed tube, tert-butyl N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate (500 mg, 2.21 mmol) was dissolved in EtOH (10 mL) and 4-chloro-6-methylpyrimidine (869 mg, 6.63 mmol) was added followed by triethylamine (894 mg, 1.23 mL, 8.84 mmol). The reaction mixture was stirred at 130° C. overnight. The crude reaction mixture was concentrated in vacuo. The residue was diluted with 20 mL of CHCl and 20 mL of water. The organic phase was extracted with CHCl (3×20 ml), dried over MgSO and concentrated in vacuo. The crude material was purified by flash chromatography (0% to 100% EtOAc in heptane) to give tert-butyl N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate as a yellow solid (496 mg, 71% yield). MS (ES+) m / z: 319.2 [(M+H) + ].

[0171] Step 2: To a pale yellow solution of tert-butyl N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate (260 mg, 817 μmol) in CHCl (8 mL) was added TFA (931 mg, 629 μl, 8.17 mmol). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The crude material was purified by ion exchange column (Si-SCX-2, 10 g, washed with MeOH and released with MeOH (NHM)) to give (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 (195 mg, 804 μmol, 98.5% yield), which was used in the next step without further purification. MS(ES+)m / z:219.2[(M+H) + ].

[0172] Intermediate 8-2: (1R,5S,8S)-3-(6-Methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine [ka]

[0173] Step 1: In a similar manner to the preparation of intermediate 8-1 (Step 1), tert-butyl N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate (2.00 g, 8.84 mmol) and 3,5-dichloropyridazine (2.0 g, 13.4 mmol) were used in the presence of Et3N (3.63 g, 5.0 mL, 35.9 mmol) at 90 °C in a sealed tube using EtOH as the solvent to give tert-butyl N-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate (1.71 g, 54%) as a white solid. MS (ES+) m / z: 339.2 [(M+H) + ].

[0174] Step 2: In a sealed tube, to a solution of tert-butyl N-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate (963 mg, 2.70 mmol) in MeOH (22 mL) was added a solution of NaOMe in methanol (25%, 1.9 mL, 8.3 mmol). The reaction mixture was heated at 85° C. overnight. The reaction mixture was adsorbed onto Isolute HM-N and column chromatography afforded tert-butyl N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate (362 mg, 38%) as a white solid. MS (ES+) m / z: 335.2 [(M+H) + ].

[0175] Step 3: (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine was prepared from tert-butyl N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate (0.93 g, 2.72 mmol) in CHCl in the presence of TFA (1.12 g, 0.76 mL, 9.86 mmol) in the same manner as in the preparation of intermediate 8-1 (Step 2). 8-2 (225 mg, 96%) was obtained as a white solid and used directly in the next step without further purification. MS (ES+) m / z: 235.2 [(M+H) + ].

[0176] Intermediate 8-3: (1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine [ka]

[0177] In a similar manner to intermediates 8-1 and 8-2, starting from tert-butyl N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate and 5-chloro-3-methyl-pyridazine, the title compound 8-3 was produced as a white solid. MS(ES+)m / z:219.3[(M+H) + ].

[0178] General procedure 1: Buchwald-type coupling reaction

[0179] To a solution of intermediate 7 (0.25 mmol) in 2-Me-THF (7 ml) in a sealed tube was added 1.0 eq. of intermediate 8. The reaction mixture was degassed and NaOtBu (1.5 eq.) was added at RT and stirring was continued for 10 min, followed by the addition of tBu-Xphos (0.06 eq.) and Pd2(dba)3 (0.03 eq.). The reaction mixture was heated at 70-80° C. until the reaction was complete (usually 1-3 h) and concentrated under vacuum. Purification was performed by either flash column chromatography or reverse phase preparative HPLC to give the desired product of formula (I).

[0180] The following Examples 1 to 64 are single enantiomers and the absolute configuration was not determined. In the examples, the enantiomers are listed in the order in which they were eluted from the column.

[0181] Example 1 and Example 2 (R)-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, and (S)-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 [ka]

[0182] Buchwald-type coupling of 2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-1 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC, afforded the title product as a white solid (Example 1). 27 mg, MS (ES+) m / z: 470.2 [(M+H) + ] and (Example 2): 28 mg, MS (ES+) m / z: 470.2 [(M + H) + ].

[0183] Examples 3 and 4 (R)-7-(3-chloro-5-fluorophenoxy)-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, and (S)-7-(3-chloro-5-fluorophenoxy)-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 [ka]

[0184] Buchwald-type coupling of 2-bromo-7-(3-chloro-5-fluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-2 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 3). : 18 mg, MS (ES+) m / z: 486.1 [(M+H) +] and (Example 4): 20 mg, MS (ES+) m / z: 486.1 [(M + H) + ].

[0185] Examples 5 and 6 (R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, and (S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine [ka]

[0186] Buchwald-type coupling of 2-bromo-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-3 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC, afforded the title product as a white solid (Example 5). : 20 mg, MS (ES+) m / z: 488.2 [(M+H) + ] and (Example 6): 20 mg, MS (ES+) m / z: 488.2 [(M + H) + ].

[0187] Examples 7 and 8 (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0188] Buchwald-type coupling of 2-bromo-8-(3-chloro-5-fluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-7 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC, afforded the title product as a white solid (Example 7). : 34 mg, MS (ES+) m / z: 500.1 [(M+H) + ] and (Example 8): 31 mg, MS (ES+) m / z: 500.1 [(M + H) + ].

[0189] Examples 9 and 10 (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0190] Buchwald-type coupling of 2-bromo-8-(3,5-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-8 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 9). : 37 mg, MS (ES+) m / z: 484.2 [(M+H) + ] and (Example 10): 36 mg, MS (ES+) m / z: 484.2 [(M + H) + ].

[0191] Example 11 and Example 12 (R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0192] Buchwald-type coupling of 2-bromo-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-9 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 11). : 42 mg, MS (ES+) m / z: 502.2 [(M+H)+ ] and (Example 12): 41 mg, MS (ES+) m / z: 502.2 [(M + H) + ].

[0193] Examples 13 and 14 (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, [ka]

[0194] Buchwald-type coupling of 2-bromo-8-(3-chloro-5-fluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-7 and (1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-3 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 13). : 32 mg, MS (ES+) m / z: 484.2 [(M+H) + ] and (Example 14): 33 mg, MS (ES+) m / z: 484.2 [(M + H) + ].

[0195] Example 15 and Example 16 (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, [ka]

[0196] Buchwald-type coupling of 2-bromo-8-(3,5-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-8 and (1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-3 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC, afforded the title product as a white solid (Example 15). 29 mg, MS (ES+) m / z: 468.2 [(M+H) + ] and (Example 16): 25 mg, MS (ES+) m / z: 468.2 [(M + H) + ].

[0197] Example 17 and Example 18 (R)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)—N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, [ka]

[0198] Buchwald-type coupling of 2-bromo-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-9 and (1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-3 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 17). 26 mg, MS (ES+) m / z: 486.2 [(M+H) + ] and (Example 18): 26 mg, MS (ES+) m / z: 486.2 [(M + H) + ].

[0199] Example 19 and Example 20 (R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, [ka]

[0200] Buchwald-type coupling of 2-bromo-8-(2,4-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-10 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 19). 28 mg, MS (ES+) m / z: 484.2 [(M+H) + ] and (Example 20): 28 mg, MS (ES+) m / z: 484.2 [(M + H) + ].

[0201] Example 21 and Example 22 (R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, [ka]

[0202] Buchwald-type coupling of 2-bromo-8-(2,3-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-15 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 21). 27 mg, MS (ES+) m / z: 484.2 [(M+H) +] and (Example 22): 26 mg, MS (ES+) m / z: 484.2 [(M + H) + ].

[0203] Example 23 and Example 24 (R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, [ka]

[0204] Buchwald-type coupling of 2-bromo-8-(3-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-11 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 23). 22 mg, MS (ES+) m / z: 482.2 [(M+H) + ] and (Example 24): 22 mg, MS (ES+) m / z: 482.2 [(M + H) + ].

[0205] Example 25 and Example 26 (R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0206] Buchwald-type coupling of 2-bromo-8-(2-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-12 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 25). 26 mg, MS (ES+) m / z: 482.2 [(M+H) + ] and (Example 26): 26 mg, MS (ES+) m / z: 482.2 [(M + H) + ].

[0207] Example 27 and Example 28 (R)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, and (S)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine [ka]

[0208] Buchwald-type coupling of 2-bromo-7-(4-chlorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-4 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 27). 36 mg, MS (ES+) m / z: 452.1 [(M+H) + ] and (Example 28): 36 mg, MS (ES+) m / z: 452.1 [(M + H) + ].

[0209] Example 29 and Example 30 (R)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, and (S)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine [ka]

[0210] Buchwald-type coupling of 2-bromo-7-(3-chlorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-5 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 29). 26 mg, MS (ES+) m / z: 452.1 [(M+H) +] and (Example 30): 25 mg, MS (ES+) m / z: 452.1 [(M + H) + ].

[0211] Example 31 and Example 32 (R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0212] Buchwald-type coupling of 2-bromo-8-(2-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-12 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 31). 20 mg, MS (ES+) m / z: 466.2 [(M+H) + ] and (Example 32): 20 mg, MS (ES+) m / z: 466.2 [(M + H) + ].

[0213] Example 33 and Example 34 (R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0214] Buchwald-type coupling of 2-bromo-8-(2,3-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-15 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 33). 36 mg, MS (ES+) m / z: 468.2 [(M+H) + ] and (Example 34): 31 mg, MS (ES+) m / z: 468.2 [(M + H) + ].

[0215] Example 35 and Example 36 (R)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, and (S)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine [ka]

[0216] Buchwald-type coupling of 2-bromo-7-(3,5-dichlorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-6 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 35). 27 mg, MS (ES+) m / z: 486.1 [(M+H) + ] and (Example 36): 27 mg, MS (ES+) m / z: 486.1 [(M + H) + ].

[0217] Example 37 and Example 38 (R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0218] Buchwald-type coupling of 2-bromo-8-(2,4-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-10 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 37). 34 mg, MS (ES+) m / z: 468.2 [(M+H) +] and (Example 38): 35 mg, MS (ES+) m / z: 468.2 [(M + H) + ].

[0219] Example 39 and Example 40 (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, and (S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine [ka]

[0220] Buchwald-type coupling of 2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-1 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 39). 32 mg, MS (ES+) m / z: 454.2 [(M+H) + ] and (Example 40): 31 mg, MS (ES+) m / z: 454.2 [(M + H) + ].

[0221] Example 41 and Example 42 (R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0222] Buchwald-type coupling of 2-bromo-8-(3-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-11 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 41). 30 mg, MS (ES+) m / z: 466.2 [(M+H) + ] and (Example 42): 28 mg, MS (ES+) m / z: 466.2 [(M + H) + ].

[0223] Example 43 and Example 44 (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0224] Buchwald-type coupling of 2-bromo-8-(3,5-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-8 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 43). 36 mg, MS (ES+) m / z: 468.2 [(M+H) + ] and (Example 44): 34 mg, MS (ES+) m / z: 468.2 [(M + H) + ].

[0225] Example 45 and Example 46 (R)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0226] Buchwald-type coupling of 2-bromo-8-(4-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-13 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 45). 27 mg, MS (ES+) m / z: 466.2 [(M+H) +] and (Example 46): 27 mg, MS (ES+) m / z: 466.2 [(M + H) + ].

[0227] Example 47 and Example 48 (R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, and (S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine [ka]

[0228] Buchwald-type coupling of 2-bromo-7-(3-chloro-5-fluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-2 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 47). 28 mg, MS (ES+) m / z: 470.1 [(M+H) + ] and (Example 48): 27 mg, MS (ES+) m / z: 470.1 [(M + H) + ].

[0229] Example 49 and Example 50 (R)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0230] Buchwald-type coupling of 2-bromo-8-(3,5-dichlorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-14 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 49). 19 mg, MS (ES+) m / z: 500.1 [(M+H) + ] and (Example 50): 18 mg, MS (ES+) m / z: 500.1 [(M + H) + ].

[0231] Example 51 and Example 52 (R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, and (S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine [ka]

[0232] Buchwald-type coupling of 2-bromo-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-3 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 51). 36 mg, MS (ES+) m / z: 472.2 [(M+H) + ] and (Example 52): 35 mg, MS (ES+) m / z: 472.2 [(M + H) + ].

[0233] Example 53 and Example 54 (R)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0234] Buchwald-type coupling of 2-bromo-8-(3,4-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-16 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 53). 35 mg, MS (ES+) m / z: 468.2 [(M+H) +] and (Example 54): 36 mg, MS (ES+) m / z: 468.2 [(M + H) + ].

[0235] Example 55 and Example 56 (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0236] Buchwald-type coupling of 2-bromo-8-(3-chloro-5-fluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-7 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 55). 26 mg, MS (ES+) m / z: 484.2 [(M+H) + ] and (Example 56): 26 mg, MS (ES+) m / z: 484.2 [(M + H) + ].

[0237] Example 57 and Example 58 (R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka]

[0238] Buchwald-type coupling of 2-bromo-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7-9 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 57). 27 mg, MS (ES+) m / z: 486.2 [(M+H) + ] and (Example 58): 29 mg, MS (ES+) m / z: 486.2 [(M + H) + ].

[0239] Example 59 and Example 60 (R)-9-(4-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, and (S)-9-(4-Fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine [ka]

[0240] Buchwald-type coupling of 2-bromo-9-(4-fluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine 7-17 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 59). 32 mg, MS (ES+) m / z: 464.2 [(M+H) + ] and (Example 60): 32 mg, MS (ES+) m / z: 464.2 [(M + H) + ].

[0241] Example 61 and Example 62 (R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, and (S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine [ka]

[0242] Buchwald-type coupling of 2-bromo-9-(2,3,4-fluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine 7-18 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 61). 36 mg, MS (ES+) m / z: 500.2 [(M+H) + ] and (Example 62): 33 mg, MS (ES+) m / z: 500.2 [(M + H) + ].

[0243] Example 63 and Example 64 (R)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, and (S)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine [ka]

[0244] Buchwald-type coupling of 2-bromo-9-(3-chloro-5-fluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine 7-19 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 using general procedure 1, followed by separation of the enantiomers by preparative chiral HPLC afforded the title product as a white solid (Example 63). 13 mg, MS (ES+) m / z: 498.2 [(M+H) + ] and (Example 64): 18 mg, MS (ES+) m / z: 498.2 [(M + H) + ].

[0245] Biological Examples

[0246] 2.1) Assay procedure: Cellular γ-secretase assay

[0247] Human glioma H4 cells overexpressing human APP695 with the Swedish double mutation (K595N / M596L) were plated at 30,000 cells / well / 100 μL in 96-well plates in IMDM containing 10% FCS, 0.2 mg / L hygromycin B and incubated at 37°C, 5% CO2. 3-4 hours after plating, compounds were diluted in media and 50 µL was added as a 1.5x concentrate to achieve final concentrations. Compound incubation was performed for 24 hours. Final doses typically ranged from 4 µM to 0.0013 µM in half-log steps, resulting in an 8-point dose-response curve. Appropriate controls using vehicle alone and reference compounds were applied in the assay. The final concentration of Me2SO was 0.4%. After incubation at 37°C and 5% CO2, the supernatant was subjected to quantification of secreted Aβ42 by AlphaLisa® assay kit (Human Amyloid beta 1-42 Kit, Perkin Elmer Inc.). 20 μl of cell culture supernatant was transferred to the assay plate. Then, 10 μL of a mixture of AlphaLisa®-bound capture antibody and biotinylated detection antibody was added, and the assay plate was incubated at room temperature for 3 hours with gentle shaking. After further addition of 20 μL of donor beads, the assay plate was incubated at room temperature for 30 minutes with constant shaking without exposure to direct light. The assay plate was then read on a Paradigm AlphaLisa® Reader using the built-in program with excitation at 680 nm and emission at 570 nm. The measured signals were then used to calculate IC values ​​for inhibition of Aβ42 secretion by nonlinear regression fitting analysis using XLfit 5.3 software (IDBS). 50 values ​​were calculated.

[0248] 2.2) Results

[0249] The table below shows the data of all compounds for inhibition of Aβ42 secretion. [Table 4]

Claims

1. Formula (I): 【Chemical 74】 (In the formula, R １ is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, or lower alkoxy substituted by halogen; When n=2 or 3, R １ may be different, m is 1, 2 or 3; n is 1, 2 or 3; Ar is the following: 【Chemistry 75】 (In the formula, R ２ is hydrogen, halogen, lower alkyl, lower alkyl substituted with halogen, or lower alkoxy; R ３ is hydrogen or halogen) is a 6-membered heteroaryl group selected from or a pharma- ceutically acceptable salt thereof.

2. The compound of formula (I) has the formula (Ia): 【Chemical 76】 (In the formula, R １ , m, n and Ar are as defined in claim 1.

2. The compound of formula (I) according to claim 1, which is a compound of the formula:

3. The compound of formula (I) has the formula (Ib): 【Chemical 77】 (In the formula, R １ , m, n and Ar are as defined in claim 1.

2. The compound of formula (I) according to claim 1, which is a compound of the formula:

4. R １ A compound of formula (I) according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein is halogen.

5. R １ A compound of formula (I) according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein is fluorine or chlorine.

6. A compound of formula (I) according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein m is 1 or 2.

7. Ar is the following: 【Chemical 78】 (In the formula, R ２ is lower alkyl or lower alkoxy; R ３ is hydrogen) The compound of formula (I) according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein R is a 6-membered heteroaryl group selected from the group consisting of:

8. Ar is the following: 【Chemical 79】 (In the formula, R ２ is methyl or methoxy, R ３ is hydrogen) The compound of formula (I) according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein R is a 6-membered heteroaryl group selected from the group consisting of:

9. R １ is a halogen, m is 1 or 2; n is 1, 2, or 3; Ar is the following: 【Chemistry 80】 (In the formula, R ２ is lower alkyl or lower alkoxy; R ３ is hydrogen) The compound of formula (I) according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein R is a 6-membered heteroaryl group selected from the group consisting of:

10. R １ is fluorine or chlorine, m is 1 or 2; n is 1, 2, or 3; Ar is the following: 【Chemistry 81】 (In the formula, R ２ is methyl or methoxy, R ３ is hydrogen) The compound of formula (I) according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein R is a 6-membered heteroaryl group selected from the group consisting of:

11. (R)-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, (S)-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, (R)-7-(3-chloro-5-fluorophenoxy)-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, (S)-7-(3-chloro-5-fluorophenoxy)-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, (R)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-9-(4-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (S)-9-(4-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (R)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (S)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine 11. The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, selected from:

12. (R)-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, (S)-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, (R)-7-(3-chloro-5-fluorophenoxy)-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, (S)-7-(3-chloro-5-fluorophenoxy)-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, (R)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, (R)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (S)—N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, (R)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and (S)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, selected from:

13. A process for preparing a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof, comprising reacting compound 7: 【Chemistry 82】 to amine 8: 【Chemistry 83】 (In the formula, Ar, R １ , n and m are as defined in any one of claims 1 to 12. to form a compound of formula (I); and If desired, converting the resulting compound into a pharma- ceutically acceptable salt thereof. The process includes:

14. A compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, when produced according to the process according to claim 13.

15. A compound according to any one of claims 1 to 12 and 14, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and 14, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

17. 15. The compound according to any one of claims 1 to 12 and 14, or a pharma- ceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, multi-infarct dementia, dementia pugilistica, or Down's syndrome.

18. 15. Use of a compound according to any one of claims 1 to 12 and 14, or a pharma- ceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, multi-infarct dementia, dementia pugilistica, or Down's syndrome.

19. 15. Use of a compound according to any one of claims 1 to 12 and 14, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, multi-infarct dementia, dementia pugilistica, or Down's syndrome.

20. A method for the therapeutic and / or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptic degeneration, hearing loss, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, multi-infarct dementia, dementia pugilistica, or Down's syndrome, comprising administering an effective amount of a compound according to any one of claims 1 to 12 and 14 or a pharma- ceutically acceptable salt thereof.

21. The invention as hereinbefore described.

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