Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators

Bioorganic & Medicinal Chemistry Letters 25 (2015) 3135–3141

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl

Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators Keita Yoshikawa ⇑, Tomofumi Ohyama, Eiki Takahashi, Yoshitaka Numajiri, Mitsuhiro Konno, Masaki Moriyama, Natsumi Takemi, Kana Kunita, Kazumi Nishimura, Ryoji Hayashi Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan

a r t i c l e

i n f o

Article history: Received 2 February 2015 Revised 15 May 2015 Accepted 1 June 2015 Available online 16 June 2015 Keywords: Metabotropic glutamate receptor mGluR5 negative allosteric modulators Acylamines

a b s t r a c t This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure–activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia. Ó 2015 Elsevier Ltd. All rights reserved.

Glutamate is major excitatory neurotransmitter in the central nervous system and plays an important role in memory, learning, and other higher brain functions.1 Metabotropic glutamate receptors (mGluRs) belong to class C of the G-protein coupled receptor superfamily.2 Currently, eight mGluR subtypes are classified into three groups (group I, mGluR1 and 5; group II, mGluR2 and 3; group III, mGluR4 and 6–8) by homology, effector mechanism, and pharmacological features.3 Localization of mGluR5 is mainly postsynaptic, and this receptor is linked via G protein to phospholipase C, which elevates intracellular calcium and activates protein kinase C.3 Recently, mGluR5 negative allosteric modulators (NAMs) have received considerable attention in pharmacological research.4 2-Methyl-6-(phenylethynyl)pyridine (MPEP; Fig. 1), which is a prototypical mGluR5 NAM,5 has shown therapeutic potential in various disease models, including anxiety,6 pain,7 gastroesophageal reflux disease,8 lower urinary tract dysfunction,9 fragile X syndrome,10 addiction,11 and levodopa-induced dyskinesia in Parkinson’s disease.12 To date, numerous mGluR5 NAMs have been identified that like MPEP have a disubstituted acetylenic structure. Some of these acetylenic mGluR5 NAMs have been studied in clinical trials (e.g., AFQ-056,13 ADX-48621,14 and RG-709015). Non-acetylenic mGluR5 NAMs have also been found that have in vitro and in vivo profiles comparable to those of acetylenic compounds. Now, non-acetylenic NAMs are attracting attention from

⇑ Corresponding author. Tel.: +81 467 32 9643; fax: +81 467 32 9931. E-mail address: [email protected] (K. Yoshikawa). http://dx.doi.org/10.1016/j.bmcl.2015.06.008 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

Figure 1. Known acetylenic mGluR5 NAMs.

researchers worldwide.16 According to recent reports, compounds 117 and 218 show excellent potential based on the results of an mGluR5 functional inhibitory assay (Fig. 2). These two compounds have different structures but a similar shape. Although the pharmacophore in these compounds was unclear, based on several relevant precedents,16,19 we hypothesized that the acyl-pyrrolidine structure of 1 and pyridyl-amino-pyridine structure of 2 were important. Thus, we designed 3 containing these two moieties from 1 and 2 (Fig. 2). Intriguingly, the overlap model of compound 1, 2 and 3 showed good similarity. Herein, we describe the hit-tolead optimization of 3 which gave novel, potent, and orally active non-acetylenic mGluR5 NAMs.

3136

K. Yoshikawa et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3135–3141

Figure 2. Flexible alignment of known non-acetylenic mGluR5 NAMs 1, 2, and designed compound 3 (MOE 2012. 10).

As shown in Scheme 1, the synthesis of 3 was started from commercially available aldehyde 4 by a reported route with modifications (Scheme 1).17,18 Amino allylation20 of 4 followed by azidation21 gave homoallyl azide 5 as a cyclization precursor. Hydroboration-mediated reductive cyclization22 of 5 provided pyrrolidine 6, and then acylation with thiazole-2-carboxylic acid gave pyrrolidine amide 7. Finally, the target 3 was prepared by Buchwald–Hartwig coupling23 of 6 with 5-amino-2-picoline to construct the pyridyl-aminopyridine structure. The inhibitory effects of compounds on human mGluR5 were investigated using HEK293 cells stably expressing human mGluR5. Briefly, cells were incubated in 2.5 lmol/L glutamate with or without each compound for 60 min. Glutamate-induced inositol phosphate (IP1) accumulation was measured using the IP-One HTRFÒ assay kit (Cisbio Bioassays, France). To our disappointment, the human mGluR5 functional inhibitory assay of 3 showed worse-than-expected activity (IC50 = 182 nM, Fig. 3). In an alternative approach, we opened the pyrrolidine ring of 3 to obtain an N-alkylated amide (8, ring-opening A, Fig. 3) and a C-alkylated amide (9, ring-opening B, Fig. 3). These two compounds were prepared from aldehyde 4 as shown in Scheme 2. After reductive amination and N-Boc protection of 4 to give N-alkylated intermediate 10, Buchwald–Hartwig coupling with 5-amino-2-picoline and replacement of the acyl group gave 8. On 9, the C-alkylated structure was constructed by treatment of sulfonylmethylcarbamate 12, which is often used as an N-acyl imine equivalent,24 with n-propylmagnesium chloride

Scheme 1. Reagents and conditions: (a) 30% NH3 solution, EtOH, rt, 1 h; allylboronic acid pinacol ester, rt, 3 h; imidazole-1-sulfonylazide hydrochloride, cat. CuSO4H2O, MeOH, rt, 3 h, 51%; (b) dicyclohexylborane, THF, rt, 16 h, 100%; (c) thiazole-2-carboxylic acid, EDCI, HOBT, DIEA, CH2Cl2, rt, 18 h, 57%; (d) 5-amino-2picoline, Pd(OAc)2, BINAP, Cs2CO3, toluene, 100 °C, 18 h, 96%.

Figure 3. Ring-opening of compound 3.

to give C-alkylated 13. The same procedure as used for 8 in Scheme 2 was applied to 9. In an in vitro study of these two types of acyclic compounds, N-alkylated 8 showed poor activity (IC50 = 584 nM, Fig. 3) but, interestingly, C-alkylated 9 showed good activity (IC50 = 28.7 nM, Fig. 3). Because of its unique structure and potential for further improvements in activity, compound 9 was considered suitable as a hit compound. Accordingly, we proceeded to a structure–activity relationship (SAR) study based on compound 9. In the initial SAR study, we focused on the n-propyl group, which was formed by pyrrolidine ring-opening. To construct a chiral center at the alpha-position of the nitrogen atom in the target compounds (Scheme 3), we used Ellman’s chiral auxiliary.25 Introduction of the chiral sulfine moiety in aldehyde 4 provided chiral imine 15. Nucleophilic addition of organometallic reagents such as organomagnesium, organozinc, and organolithium compounds to 15 afforded 16a–m as diastereomeric mixtures. As shown in Table 1, there was variability in the isolated yields and diastereoselectivity with respect to the substrate and organometallic reagent. After separation of the diastereomers, Buchwald–Hartwig coupling of each diastereomer of 16a–m with 5-amino-2-picoline to construct pyridyl-aminopyridine structure followed by solvolysis of the sulfine moiety gave (S)- or (R)-amines (18a–m) as single enantiomers. Finally, the target compounds were prepared by acylation of (S)- or (R)-18a–m with thiazole-2carbonyl chloride and treated with hydrochloride to give as the hydrochloride salts. The absolute configuration of the chiral center in (R)-19b was determined by single-crystal X-ray diffraction analysis (Fig. 4). Moreover, the absolute configurations of the other compounds were determined by comparison of 1H NMR spectra of (R,R)-16b or (R,S)-16b with corresponding diastereomers of sulfinamides 16a–m and comparison of polarity of both diastereomers 16a–m in thin-layer chromatography analysis. We identified the (R)-enantiomers as the favorable configuration by comparison of several target compounds ((R)-19a versus (S)-19a, (R)-19b versus (S)-19b, (R)-19d versus (S)-19d, and (R)-19g versus (S)-19g, Table 2) in human mGluR5 functional inhibitory assays. Thus, we next prepared a minimal library with the various (R)-enantiomers shown in Table 2. It was found that (R)-19b (n-propyl), (R)-19d (i-propyl), (R)-19f (cyclopropyl), (R)-19g (cyclobutyl), and (R)-19k (3-butenyl) showed activity more than threefold that of MPEP (IC50 <10 nM, Table 2). Furthermore, (R)19j (2-propenyl) showed the highest activity of these compounds. However, (R)-19a (ethyl), (R)-19c (n-butyl), (R)-19e (t-butyl), (R)19h (cyclopentyl), and (R)-19i (cyclohexyl) showed activity similar to that of MPEP. These results suggest that there is a preferable range of substituent size for realizing good activity. Introduction

3137

K. Yoshikawa et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3135–3141

Scheme 2. Reagents and conditions: (a) n-PrNH2, Na2SO4, toluene, rt, 4 h; NaBH4, MeOH, rt, 1 h; Boc2O, Et3N, CH2Cl2, rt, 10 h, 86%; (b) 5-amino-2-picoline, Pd(OAc)2, BINAP, Cs2CO3, toluene, 100 °C, 5 h, 77%; (c) TFA, CH2Cl2, rt, 2 h; thiazole-2-carboxylic acid, HATU, Et3N, CH2Cl2, rt, 2 h, 94%; (d) sodium benzenesulfinate, t-butyl carbamate, HCO2H, THF, H2O, 91%; (e) n-PrMgCl, THF, 0 °C, 1 h, 56%; (f) 5-amino-2-picoline, Pd(OAc)2, BINAP, Cs2CO3, toluene, 100 °C, 5 h, 84%; (g) TFA, CH2Cl2, rt, 2 h; thiazole-2-carboxylic acid, HATU, Et3N, CH2Cl2, rt, 2 h, 81%.

Scheme 3. Reagents and conditions: (a) Cs2CO3, CH2Cl2, reflux, 14 h, 98%; (b) organometallic reagent, THF, 78 °C, Table 1; (c) Pd(OAc)2, BINAP, Cs2CO3, toluene, 100 °C, 5 h, 35–99%; (d) 4 M HCl/1,4-dioxane, MeOH, 72–99%; (e) thiazole-2-carbonyl chloride, Et3N, CH2Cl2, rt, 2 h, or thiazole-2-carboxylic acid, HATU, Et3N, CH2Cl2, rt, 2 h, 51–99%; (f) 10% HCl/MeOH, 62–99%.

Table 1 Yield data

R

Compounds (yields)a

1

Ethyl

(R,R)-16a (72%)/(R,S)-16a (26%)

2

n-Propyl

(R,R)-16b (58%)/(R,S)-16b (38%)

3

n-Butyl

(R,R)-16c (70%)/(R,S)-16c (16%)

4

i-Propyl

(R,R)-16d (50%)/(R,S)-16d (36%)

Entry

Reagents

(continued on next page)

3138

K. Yoshikawa et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3135–3141 Table 1 (continued) R

Compounds (yields)a

5

t-Butyl

(R,R)-16e (11%)/(R,S)-16e (36%)

6

Cyclopropyl

(R,R)-16f (35%)/(R,S)-16f (50%)

7

Cyclobutyl

(R,R)-16g (38%)/(R,S)-16g (28%)

8

Cyclopentyl

(R,R)-16h (58%)/(R,S)-16h (trace)

9

Cyclohexyl

(R,R)-16i (30%)/(R,S)-16i (24%)

10

2-Propenyl

(R,R)-16j (54%)/(R,S)-16j (trace)

11

3-Butenyl

(R,R)-16k (52%)/(R,S)-16k (27%)

12

Benzyl

(R,R)-16l (80%)/(R,S)-16l (6%)

13

Methoxymethyl

(R,R)-16m (23%)/(R,S)-16m (trace)

Entry

a

Reagents

Isolated yield.

Figure 4. X-ray structure of (R)-19b (ORTEP drawing; green, chlorine; red, oxygen; blue, nitrogen; yellow, sulfur).

of other substituents such as benzyl ((R)-19n) and methoxymethyl ((R)-19o) groups resulted in worse activity. To prepare the next sub-library based on the thiazole moiety and 2-picoline moiety in (R)-19b, we planned a new synthetic pathway, shown in Scheme 4. Diastereoselective nucleophilic addition to 15 was accomplished with good selectivity by using the zinc ate complex derived from n-propylmagnesium chloride and zinc chloride. After recrystallization to obtain the single diastereomer (R,R)-16b and the same procedure as shown in Scheme 3, acylation of (R)-18b with several acyl moieties and hydrochlorination gave target compounds 20a–g. Coupling precursor 22 was obtained from (R,R)-16b in two steps (solvolysis and acylation); then, several amino-aryl moieties were introduced and hydrochlorination gave target compounds 23a–g. A human mGluR5 functional assay of compounds 20a–g and 23a–g showed no clear SAR and no improvement in activity, though the activity of 20d, 23c, and 23d was comparable to that of (R)-19b (Table 3). Derivatization with a thiazole moiety showed that heteroaromatics could be tolerated. We assessed the anxiolytic-like activity of (R)-19b and (R)-19j in a mouse model of stress-induced hyperthermia (SIH).26,27 In the SIH procedure, exaggerated responses of the autonomic nervous system to stress or anxiety are measured using rectal temperature measurements in mice.28 Following oral administration, (R)-19b produced a significant attenuation of the SIH response at 3 and 10 mg/kg, while having no effect on the basal rectal temperature (Fig. 5). Furthermore, (R)-19j, which showed the highest activity in the in vitro assay, significantly attenuated the SIH response at 1 mg/kg without affecting basal temperature

Table 2 Human mGluR5 functional inhibitory activity (IC50)

a

Compound

R

hmGluR5 IC50a (nM)

MPEP (R)-19a (S)-19a (R)-19b (S)-19b (R)-19c (R)-19d (S)-19d (R)-19e (R)-19f (R)-19g (S)-19g (R)-19h (R)-19i (R)-19j (R)-19k (R)-19l (R)-19m

— Ethyl Ethyl n-Propyl n-Propyl n-Butyl i-Propyl i-Propyl t-Butyl Cyclopropyl Cyclobutyl Cyclobutyl Cyclopentyl Cyclohexyl 2-Propenyl 3-Butenyl Benzyl Methoxymethyl

32.0 15.4 >1000 8.2 978 30.9 7.5 1055 30.9 9.7 9.3 >1000 16.6 37.8 2.4 8.8 55.5 55.9

IC50 values were determined by IP1 accumulation assay in vitro (n = 2).

(Fig. 6). These results suggest that (R)-19b and (R)-19j have an anxiolytic-like effect in vivo. Further optimization of these

3139

K. Yoshikawa et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3135–3141

Scheme 4. Reagents and conditions: (a) THF, 0 °C, 93:7 (1H NMR crude ratio), 88% (isolated yield); (b) aryl carbonyl chloride, Et3N, CH2Cl2, rt, 2 h; thiazole-2-carbonyl chloride, Et3N, CH2Cl2, rt, 2 h; (c) aryl carboxylic acid, HATU, Et3N, CH2Cl2, rt, 2 h; (d) 10% HCl/MeOH; (e) 4 M HCl/1,4-dioxane, MeOH; (f) thiazole-2-carbonyl chloride, Et3N, CH2Cl2, rt, 2 h, 98% in 2 steps; (g) aryl amine, Pd(OAc)2, BINAP, Cs2CO3, toluene, 100 °C.

Table 3 Human mGluR5 functional inhibitory activities (IC50)

hmGluR5 IC50a (nM)

Compound

20a

30% inhibition (100 nM)

23a

NA

20b

27.8

23b

71.4

20c

31.2

23c

13.3

20d

10.0

23d

12.8

20e

49% inhibition (100 nM)

23e

31% inhibition (100 nM)

20f

42.2

23f

60.0

20g

23.3

23g

43.9

Compound

a

Ar

Ar0

hmGluR5 IC50a (nM)

IC50 values were determined by IP1 accumulation assay in vitro (n = 2).

compounds and study of the efficacy in other animal models will be reported in due course. In conclusion, we identified a series of novel non-acetylenic mGluR5 NAMs based on the alpha-substituted acylamine structure, which were derived by ring-opening of the pyrrolidine structure in 3. The preferred stereochemistry at the chiral center was found to

be the (R)-configuration. Compounds (R)-19b and (R)-19j showed good activity (IC50 <10 nM) in a human mGluR5 functional inhibitory assay. These compounds exhibited anxiolytic-like effects in a mouse SIH model when administered orally. We believe these compounds show promise as therapeutic agents for anxiety disorder.

3140

K. Yoshikawa et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3135–3141

Figure 5. Effects of (R)-19b on basal rectal temperature (A) and SIH response (B) in mice. Vehicle (0.5% methylcellulose) or (R)-19b was administered orally 1 h before the first rectal temperature measurement (T1). The second rectal temperature (T2) measured 10 min after T1 measurement. The SIH response was defined as T2–T1. Data are presented as the mean ± standard error of the mean (SEM) (n = 10). ⁄p <0.025 (one-tailed Williams’ test vs vehicle).

Figure 6. Effects of (R)-19j on basal rectal temperature (A) and SIH response (B) in mice. Vehicle (0.5% methylcellulose) or (R)-19j was administered orally 1 h before the first rectal temperature measurement (T1). The second rectal temperature (T2) measured 10 min after T1 measurement. The SIH response was defined as T2–T1. Data are presented as the mean ± standard error of the mean (SEM) (n = 10). ⁄p <0.025 (one-tailed Williams’ test vs vehicle).

Acknowledgments The authors thank Tomohide Masuda for preparing the overlap model. The authors would also like to thank Hirozumi Takahashi for performing X-ray structural analysis. Keita Yoshikawa thanks Yuji Sugawara for his helpful advice. Supplementary data

2. 3. 4.

5.

The X-ray crystallography data of compound (R)-19b in this Letter has been deposited with the Cambridge Crystallography Data Centre as supplementary publications No. CCDC 1045944. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmcl. 2015.06.008.

10.

References and notes

11. 12.

1. (a) Robinson, M. B.; Coyle, J. T. FASEB J. 1987, 1, 446; (b) Daggett, L. P.; Sacaan, A. I.; Akong, M.; Rao, S. P.; Hess, S. D.; Liaw, C.; Urrutia, A.; Jachec, C.; Ellis, S. B.;

6. 7. 8. 9.

13.

Dreessen, J. Neuropharmacology 1995, 34, 871; (c) Knöpfel, T.; Kuhn, R.; Allgeier, H. J. Med. Chem. 1995, 38, 1417. Pin, J.-P.; Duvoisin, R. Neuropharmacology 1995, 34, l. Kunishima, N.; Shimada, Y.; Tsuji, Y.; Sato, T.; Yamamoto, M.; Kumasaka, T.; Nakanishi, S.; Jingami, H.; Morikawa, K. Nature 2000, 407, 971. (a) Spooren, W.; Gasparini, F.; Salt, T. E.; Kuhn, R. Trends Pharmacol. Sci. 2001, 22, 331; (b) Rocher, J.-P.; Bonnet, B.; Boléa, C.; Lütjens, R.; Le Poul, E.; Poli, S.; Epping-Jordan, M.; Bessis, A.-S.; Ludwig, B.; Mutel, V. Curr. Top. Med. Chem. 2011, 11, 680. Gasparini, F.; Lingenhöhl, K.; Stoehr, N.; Flor, P. J.; Heinrich, M.; Vranesic, I.; Biollaz, M.; Allgeier, H.; Heckendorn, R.; Urwyler, S.; Varney, M. A.; Johnson, E. C.; Hess, S. D.; Rao, S. P.; Sacaan, A. I.; Santori, E. M.; Veliçelebi, G.; Kuhn, R. Neuropharmacology 1999, 38, 1493. Spooren, W. P. J. M.; Vassout, A.; Neijt, H. C.; Kuhn, R.; Gasparini, F.; Roux, S.; Porsolt, R. D.; Gentsch, C. Pharmacol. Exp. Ther. 2000, 295, 1267. Zhu, C. Z.; Wilson, S. G.; Mikusa, J. P.; Wismer, C. T.; Gauvin, D. M.; Lynch, J. J.; Wade, C. L.; Decker, M. W.; Honore, P. Eur. J. Pharmacol. 2004, 506, 107. Jensen, J.; Lehmann, A.; Uvebrant, A.; Carlsson, A.; Jerndal, G.; Nilsson, K.; Frisby, C.; Blackshaw, L. A.; Mattsson, J. P. Eur. J. Pharmacol. 2005, 519, 154. Guarneri, L.; Poggesi, E.; Angelico, P.; Farina, P.; Leonardi, A.; Clarke, D. E.; Testa, R. BJU Int. 2008, 102, 890. Yan, Q. J.; Rammal, M.; Tranfaglia, M.; Bauchwitz, R. P. Neuropharmacology 2005, 49, 1053. Olive, M. F. Curr. Drug Abuse Rev. 2009, 2, 83. Mela, F.; Marti, M.; Dekundy, A.; Danysz, W.; Morari, M.; Cenci, M. A. J. Neurochem. 2007, 101, 483. Berg, D.; Godau, J.; Trenkwalder, C.; Eggert, K.; Csoti, I.; Storch, A.; Huber, H.; Morelli-Canelo, M.; Stamelou, M.; Ries, V.; Wolz, M.; Schneider, C.; Di Paolo, T.;

K. Yoshikawa et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3135–3141

14.

15.

16. 17. 18. 19.

Gasparini, F.; Hariry, S.; Vandemeulebroecke, M.; Abi-Saab, W.; Cooke, K.; Johns, D.; Gome-Mancilla, B. Mov. Disord. 2011, 26, 1243. Rocher, J.-P.; Bonnet, B.; Bolea, C.; Lutjens, R.; Le Poul, E.; Poli, S.; EppingJordan, M.; Bessis, A.-S.; Ludwig, B.; Mutel, V. Curr. Top. Med. Chem. 2011, 11, 680. Jaeschke, G.; Kolczewski, S.; Spooren, W.; Vieira, E.; Bitter-Stoll, N.; Boissin, P.; Borroni, E.; Büttelmann, B.; Ceccarelli, S.; Clemann, N.; David, B.; Funk, C.; Guba, W.; Harrison, A.; Hartung, T.; Honer, M.; Huwyler, J.; Kuratli, M.; Niederhauser, U.; Pähler, A.; Peters, J.-U.; Petersen, A.; Prinssen, E.; Ricci, A.; Rueher, D.; Rueher, M.; Schneider, M.; Spurr, P.; Stoll, T.; Tännler, D.; Wichmann, J.; Porter, R. H.; Wettstein, J. G.; Lindemann, L. J. Med. Chem. 2015, 58, 1358. Emmitte, K. A. ACS Chem. Neurosci. 2011, 2, 411. Weiss, J. M.; Jimenez, H. N.; Li, G.; April, M.; Uberti, M. A.; Bacolod, M. D.; Brodbeck, R. M.; Doller, D. Bioorg. Med. Chem. Lett. 2011, 21, 4891. Spanka, C.; Glatthar, R.; Desrayaud, S.; Fendt, M.; Orain, D.; Troxler, T.; Vranesic, I. Bioorg. Med. Chem. Lett. 2010, 20, 184. These moieties were also used in the following references. (a) Wágner, G.; Wéber, C.; Nyéki, O.; Nógrádi, K.; Bielik, A.; Molnár, L.; Bobok, A.; Horváth, A.; Kiss, B.; Kolok, S.; Nagy, J.; Kurkó, D.; Gál, K.; Greiner, I.; Szombathelyi, Z.; } , G. M.; Dómany, G. Bioorg. Med. Chem. Lett. 2010, 20, 3737; (b) Lamb, J. Keseru P.; Engers, D. W.; Niswender, C. M.; Rodriguez, A. L.; Venable, D. F.; Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2011, 21, 2711; (c) Carcache, D.;

20. 21. 22. 23. 24. 25. 26.

27.

28.

3141

Vranesic, I.; Blanz, J.; Desrayaud, S.; Fendt, M.; Glatthar, R. ACS Med. Chem. Lett. 2011, 2, 58. Sugiura, M.; Hirano, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 7182. Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797. Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1987, 109, 7151. 0 Ahman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363. Å Morton, J.; Rahim, A.; Walker, E. R. H. Tetrahedron Lett. 1982, 23, 4123. Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913. Physical data for (R)-19b HCl salt: 1H NMR (400 MHz, CDCl3) d (ppm): 0.99 (3H, t, J = 7.3 Hz), 1.35–1.51 (2H, m), 1.82–2.00 (2H, m), 2.81 (3H, s), 5.01–5.07 (1H, m), 7.42 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 8.0 Hz), 7.60 (1H, d, J = 3.1 Hz), 7.66 (1H, d, J = 2.2 Hz), 7.76 (1H, s), 7.88 (1H, d, J = 3.1 Hz), 8.17 (1H, d, J = 2.2 Hz), 8.48–8.51 (1H, m), 9.36 (1H, br s); ESI-MS: m/z = 402 ([M+H]+); melting point: 144–150 °C. Physical data for (R)-19j HCl salt: 1H NMR (400 MHz, CD3OD) d (ppm): 2.10– 2.19 (4H, m), 2.70 (3H, s), 5.00–5.07 (3H, m), 5.82–5.91 (1H, m), 7.78 (1H, d, J = 8.6 Hz), 7.85 (1H, d, J = 3.0 Hz), 7.95 (1H, d, J = 2.3 Hz), 7.98 (1H, d, J = 3.0 Hz), 8.26 (1H, d, J = 2.3 Hz), 8.62–8.65 (1H, m), 9.18 (1H, d, J = 8.2 Hz), 9.42 (1H, br s); ESI-MS: m/z = 414 ([M+H]+); melting point: 124–126 °C. (a) Bouwknecht, A. J.; Olivier, B.; Paylor, R. E. Neurosci. Biobehav. Rev. 2007, 31, 41; (b) Satow, A.; Maehara, S.; Ise, S.; Hikichi, H.; Fukushima, M.; Suzuki, G.; Kimura, T.; Tanaka, T.; Ito, S.; Kawamoto, H.; Ohta, H. J. Pharmacol. Exp. Ther. 2008, 326, 577.