Discovery of novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives as c-secretase modulators Takafumi Takai ⇑ , Yasutaka Hoashi, Yoshihide Tomata, Sachie Morimoto, Minoru Nakamura, Tomomichi Watanabe, Tomoko Igari, Tatsuki Koike Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan article info Article history: Received 13 May 2015 Revised 27 July 2015 Accepted 30 July 2015 Available online 7 August 2015 Keywords: c-Secretase modulators Alzheimer’s disease Amyloid beta abstract Novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives were designed, synthesized, and evalu- ated as c-secretase modulators (GSMs). An optimization study of this series resulted in the identification of (R)-11j, which showed a potent Ab 42 -lowering effect, high bioavailability and good blood–brain barrier permeability in mice. Oral administration of (R)-11j significantly reduced brain Ab 42 in mice at a dose of 10 mg/kg. Ó 2015 Elsevier Ltd. All rights reserved. Alzheimer’s disease (AD) is an age-associated neurodegenera- tive disorder characterized by impaired memory and cognition. 1 A characteristic pathology of AD is the formation of plaques with the accumulation of amyloid beta (Ab), which is produced by step- wise processing of the amyloid precursor protein (APP) by b-secre- tase and c-secretase. 2 Because c-secretase also cleaves other substrates in addition to APP, such as Notch, 3 it was reported that c-secretase inhibitor induced several toxicities in clinical trials. 4 c-Secretase modulators (GSMs) lower pathogenic Ab by cleavage shift without affecting Notch signal and have been proposed as a potential therapeutic agent for AD. 5 We recently reported the potent piperazine derivative 1 as a GSM, which selectively reduced brain Ab 42 levels in normal mice (Fig. 1). 6 In the study, the oxa- zolylphenyl moiety in 1 was validated as a suitable surrogate for the imidazolylphenyl moiety, a highly conserved component across GSMs from several research laboratories. 5 To identify a novel class of GSM, the oxazolylphenyl moiety was introduced into various right side fragments in reported GSMs, such as the 3-ben- zyl-1,2,4-triazole in compound 2. 7 As a result, we observed that the 1,2,4-triazole derivative 3 showed moderate Ab 42 -lowering activity (Fig. 1). A recent analysis of GSMs indicated that their increased lipophilicity enhanced their potency but reduced their drug-like- ness. 8 Here we describe lead generation from 3 using ligand- lipophilicity efficiency (LLE) as a drug-likeness guideline, and the structure–activity relationship (SAR) of novel 5,6,7,8-tetrahydro [1,2,4]triazolo[4,3-a]pyridines. Monocyclic 1,2,4-triazole derivative 3 was synthesized as shown in Scheme 1. Bromide 12 6 was converted to nitrile 13, which was coupled with hydrazide 14 and subsequently cyclized to afford 3. The synthetic route for the preparation of the tetrahydro[1,2,4]- triazolo[1,5-a]pyridine derivative 4 is illustrated in Scheme 2. Hydrolysis of the cyano group of 13 yielded benzoic acid 15. Coupling 15 with t-butyl carbazate and subsequent N-Boc depro- tection afforded hydrazide 16a as an HCl salt form. Hydrazide 16b was also directly obtained as a free form by condensation of 15 with hydrazine monohydrate. Imidate 19 was prepared by alky- lation of phenylacetonitrile 17, followed by ethanolysis of 18 under acidic conditions. Finally, ring formation using 16a and 19 in the presence of imidazole gave the tetrahydro[1,2,4]triazolo[1,5-a]pyr- idine derivative 4. Tetrahydro[1,2,4]triazolo[4,3-a]pyridine and related bicyclic analogs 5 and 7–10 were synthesized as shown in Scheme 3. Alkylation of the benzyl position of phenylacetic acid 20 with 1-bromoalkanes 21a–c afforded 22a–c. Benzohydrazide 16a or 16b was acylated with 22a–d to give diacyl compounds 23a–d, which were cyclized by treatment with CCl 4 and PPh 3 to yield oxa- diazoles 24a–d. Alkylchloride 24a–d were subjected to nucle- ophilic azidation, followed by reduction of the azide group to give the primary amines 25a–d. Intracyclization of 25a–d pro- ceeded smoothly under acidic conditions to provide the annulate derivatives 5, 7, 8, and 10. Synthesis of dihydro[1,2,4]triazolo http://dx.doi.org/10.1016/j.bmcl.2015.07.101 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +81 466 32 1133; fax: +81 466 29 4454. E-mail address: takafumi.takai@takeda.com (T. Takai). Bioorganic & Medicinal Chemistry Letters 25 (2015) 4245–4249 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl