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γ dual agonists
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Chinese Chemical Letters 19 (2008) 166–168 www.elsevier.com/locate/cclet
Synthesis of urea acetates as potential PPARa/g dual agonists Chang Yan Zhao a,b, Chang Qing Shi a,b, Yuan Wei Chen a,* a
Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China b Graduate School of Chinese Academy of Sciences, Beijing 100049, China Received 28 September 2007
Abstract In the quest for novel PPARa/g dual agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we designed and synthesized a series of urea acetates as potential PPARa/g dual agonists. The structure of the target compounds, intermediates were characterized by 1H NMR, HRMS. # 2007 Yuan Wei Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Oxazole; PPAR agonist; Type 2 diabetes; Urea; Ammonolysis; Synthesis
The nuclear receptor peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity and diabetes [1]. There are three PPAR subtypes which designated PPARa, PPARg and PPARd. The fibrate class of hypolipidemic drugs act through PPARa [2] and the thiazolidinedione class of anti-diabetic agents act through PPARg [3]. Synchronized therapies which concurrently control diabetes and inhibit progression of cardiovascular complications may be a fascinating therapeutic option in the treatment of diabetes. Therefore, PPARa/g dual agonists are under development to prevent diabetic cardiovascular complications. A number of PPARa/g dual agonists have appeared in the literature [4] and some of them are currently in clinical development. The compounds of PPARa/g dual agonists have a few essential pharmacophore elements. These comprise of an acidic group linked to a central flat ring and a large lipophilic substructure [5]. In order to search for more potent PPARa/g dual agonists, to study the structure– activity relationship of them and eventually to develop anti-diabetic agents, a novel series of urea acetates were designed and synthesized as Scheme 1. The starting material thiophene 3-carboxamide condensated with ethyl 4-bromo-3-oxopentanoate to provide ethyl 2-(5-methyl-2-(thiophen-3-yl)oxazol-4-yl) acetate, which can be easily purified by column chromatography. Reduction of ester 2 by LiAlH4 in THF produced the corresponding alcohol in high yield. Subsequent mesylation of the alcohol provided the methylsulfonate 3 quantitively. The 4-(2-(5-methyl-2-(thio-phen-3-yl)oxazol-4-yl)ethoxy)benzahyde 4 was obtained by the coupling of methylsulf-onate 3 with 4-hydroxylbenzaldehyde in CH3CN in the presence of potassium carbonate. Then, aldehyde 5 reacted with glycine methyl ester hydrochloride and sodium cyanoboro hydride in methanol to afford amino ester 6 in 90% yields. With the compound 6 in hand, a series of
* Corresponding author. E-mail address: [email protected] (Y.W. Chen). 1001-8417/$ – see front matter # 2007 Yuan Wei Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2007.12.013
C.Y. Zhao et al. / Chinese Chemical Letters 19 (2008) 166–168
167
Scheme 1. Reagents and conditions: (a) ethyl 4-bromo-3-oxopentanoate, toluene, reflux, 4 h, 51%; (b) THF, LAH, 0 8C, 2 h, >90%; (c) MeSO2Cl, Et3N, CH2Cl2, 25 8C, 2 h, >98%; (d) 4-hydroxybenzaldehyde, K2CO3, CH3CN, 80 8C, 24 h, 95%; (e) glycine methyl ester hydrochloride, anhydrous MgSO4, methanol, 0 8C, 0.5 h; NaCNBH3, 70 8C, 8 h, 90%; (f) R–PhNHCH3, triphosgene, Et3N, CH3CN, 0–25 8C, 12 h, 20–60%; (g) LiOHH2O, THF/H2O (1:1), 25 8C, 3 h, >95%.
substituted N-methyl benzenamines were used for the synthesis ureido esters 7. N-Methylbenzenamines was carbonylated with triphosgene in the presence of triethyl-amine, followed by addition of amino esters 6 in situ to give the desired ureido esters 7. Ureido esters 7 were hydrolyzed to provide the target compound 8 quantitatively. In conclusion, we have synthesized a series of urea acetates 8 in good yields via oxazole formation, coupling reaction, carbonylation and hydrolysis. These compounds contain a wide range of substitution patterns and were fully characterized. Moreover, we used N-methyl benzenamines which react with amino ester 6 to provide urea esters 7, this successfully prevented the ammonolysis of ester 6 to produce amide, see Ref. [6]. Functional activity assay of these compounds are currently in progess. Acknowledgments The authors thank the 100 Talents program of Chinese Academy of Sciences, the Chengdu Institute of Organic Chemistry, and the Graduate School of the Chinese Academy of Sciences for financial support of this work. References [1] [2] [3] [4]
D.E. Moller, Nature 414 (2001) 821. P.J. Brown, et al. J. Med. Chem. 42 (1999) 3785. J.M. Lehmann, L.B. Moore, T.A. Simth-Oliver, W.O. Wilkison, T.M. Willson, S.A. Kliewer, J. Biol. Chem. 270 (1995) 12953. (a) B.R. Henke, J. Med. Chem. 47 (2004) 4118; (b) Y. Lu, et al. Bioorg. Med. Chem. Lett. 16 (2006) 915; (c) P.V. Devasthale, et al. Bioorg. Med. Chem. Lett. 17 (2007) 2312. [5] B. Kuhn, et al. Bioorg. Med. Chem. Lett. 16 (2006) 4016.
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[6] Ammonolysis of amino ester in carbonylation was observed in our experiments, and the reaction product is characterized as follows:
1H NMR (300 Hz, CDCl3) dppm): 7.59 (m, 2H), 7.34 (m, 2H), 7.16 (m, 2H), 6.83 (m, 2H), 4.55 (s, 2H), 3.87 (s, 2H), 0.99 (s, 9H), 0.20 (s, 6H).; (8a) 1H NMR (300 Hz,CDCl3, dppm): 7.85 (dd, 1H, J = 3.0, 1.2 Hz), 7.56 (dd, 1H, J = 5.0, 1.2 Hz), 7.33–7.36 (m, 1H), 7.14–7.20 (m, 2H), 6.88– 6.97 (m, 2H), 6.69–6.79 (m, 4H), 4.14 (t, 2H, J = 6.6Hz), 4.08 (s, 2H), 3.83 (s, 3H), 3.69 (s, 2H), 3.14 (s, 3H), 2.92 (t, 2H, J = 6.6 Hz), 2.33 (s, 3H); HRMS (ESI, m/z): Calcd for [C28H29N3O6S + Na]+, 558.1669 found, 558.168; (8b) 1H NMR(300 Hz,CDCl3, dppm): 7.87 (dd, 1H, J = 3.0, 1.2 Hz), 7.55 (dd, 1H, J = 5.0, 1.2 Hz), 7.32–7.36 (m, 3H), 7.20–7.29 (m, 2H), 7.10– 7.15 (m, 1H), 6.89 (d, 2H, J = 8.6 Hz), 6.76 (d, 2H, J = 8.6 Hz), 4.16 (t, 2H, J = 6.6 Hz), 4.15 (s, 2H), 3.75 (s, 2H), 3.24 (s, 3H), 2.94 (t, 2H, J = 6.6 Hz), 2.33 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H27N3O5S + Na]+, 528.1564 found, 528.1557; (8c) 1H NMR (300 Hz,CDCl3, dppm): 7.87 (dd, 1H, J = 3.0, 1.2 Hz), 7.56 (dd, 1H, J = 5.0, 1.2 Hz), 7.33–7.36 (m, 1H), 7.21–7.29 (m, 1H), 7.00– 7.03 (m, 2H), 6.92–6.97 (m, 2H), 6.76–6.79 (m, 3H), 4.10–4.17 (m, 4H), 3.79 (s, 2H), 3.22 (s, 3H), 2.95 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H26FN3O5S + Na]+, 546.1469 found, 546.1456; (8d) 1H NMR (300 Hz, CDCl3, dppm): 7.86 (dd, 1H, J = 3.0, 1.0 Hz), 7.56 (dd, 1H, J = 5.0, 1.0 Hz), 7.34–7.36 (m, 1H), 7.18–7.24 (m, 1H), 6.90 (d, 2H, J = 8.6 Hz), 6.74–6.79 (m, 4H), 6.67 (d, 1H, J = 7.9 Hz), 4.14–4.17 (m, 4H), 3.99 (q, 2H, J = 6.9 Hz), 3.78 (s, 2H), 3.25 (s, 3H), 2.94 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H), 1.37 (t, 3H, J = 6.9 Hz); HRMS (ESI, m/z): Calcd for [C29H31N3O6S + Na]+, 572.1826 found, 572.1837; (8e) 1H NMR (300 Hz,CDCl3, dppm): 7.88 (d, 1H, J = 2.7 Hz), 7.56 (dd, 1H, J = 5.0, 1.0 Hz), 7.33–7.41 (m, 3H), 7.11 (d, 2H, J = 8.6 Hz), 6.92 (d, 2H, J = 8.6 Hz), 6.77 (d, 2H, J = 8.6 Hz), 4.17 (s, 2H, J = 6.6 Hz), 4.15 (s, 2H), 3.77 (s, 2H), 3.20 (s, 3H), 2.96 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H26BrN3O5S + Na]+, 606.0669 found, 606.0691/608.0672; (8f) 1H NMR (300 Hz, CDCl3, dppm): 7.87 (dd, 1H, J = 3.0, 1.1 Hz), 7.56 (dd, 1H, J = 5.0, 1.1 Hz), 7.34–7.37 (m, 1H), 7.26–7.29 (m, 2H), 7.14– 7.18 (m, 2H), 6.90 (d, 2H, J = 8.6 Hz), 6.77 (d, 2H, J = 8.6 Hz), 4.16 (s, 2H, J = 6.6 Hz), 4.13 (s, 2H), 3.79 (s, 2H), 3.21 (s, 3H), 2.95 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H26ClN3O5S + Na]+, 562.1174 found, 562.1163; (8g) 1H NMR (300 Hz,CDCl3, dppm): 7.86 (dd, 1H, J = 3.0, 1.1 Hz), 7.56 (dd, 1H, J = 5.0, 1.1 Hz), 7.34–7.35 (m, 1H), 7.07–7.14 (m, 4H), 6.86 (d, 2H, J = 8.6 Hz), 6.75 (d, 2H, J = 8.6 Hz), 4.16 (t, 2H, J = 6.6 Hz), 4.08 (s, 2H), 3.74 (s, 2H), 3.23 (s, 3H), 2.93 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H), 2.28 (s, 3H); HRMS (ESI, m/z): Calcd for C28H29N3O5S, 542.1720 found, 542.1735. HRMS (ESI, m/z): Calcd for [C28H29N3O5S + Na]+, 542.1720 found, 542.1735; (8h) 1H NMR (300 Hz,CDCl3, ppm): d 7.87 (dd, 1H, J = 3.0, 1.1 Hz), 7.56 (dd, 1H, J = 5.0, 1.1 Hz), 7.34–7.37 (m, 1H), 7.17–7.22 (m, 2H), 7.00 (t, 2H, J = 8.0 Hz), 6.90 (d, 2H, J = 8.6 Hz), 6.75–6.78 (m, 2H), 4.16 (t, 2H, J = 6.6 Hz), 4.10 (s, 2H), 3.76 (s, 2H), 3.20 (s, 3H), 2.95 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H26FN3O5S + Na]+, 546.1469 found, 546.1456; (8i) 1H NMR (300 Hz,CDCl3, dppm): 7.89 (dd, 1H, J = 3.0, 1.1 Hz), 7.55–7.59 (m, 2H), 7.34–7.38 (m, 3H), 6.92 (d, 2H, J = 8.6 Hz), 6.78 (d, 2H, J = 8.6 Hz), 4.08–4.18 (m, 4H), 3.85 (s, 2H), 3.23 (s, 3H), 2.96 (t, 2H, J = 6.6 Hz), 2.35 (s, 3H); HRMS (ESI, m/z): Calcd for [C28H25ClF3N3O6S + Na]+, 630.1048 found, 630.1048/632.1014; (8j) 1H NMR (300 Hz,CDCl3, dppm): 7.88 (dd, 1H, J = 3.0, 1.1 Hz), 7.56 (dd, 1H, J = 5.0, 1.1 Hz), 7.34–7.37 (m, 1H), 7.21–7.26 (m, 2H), 7.06– 7.14 (m, 2H), 6.92 (d, 2H, J = 8.6 Hz), 6.78 (d, 2H, J = 8.6 Hz), 4.08–4.18 (m, 4H), 3.08 (s, 2H), 3.24 (s, 3H), 2.95 (t, 2H, J = 6.6Hz), 2.34 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H26ClN3O5S + Na]+, 562.1174 found, 562.1163; (8k) 1H NMR (300 Hz,CDCl3, dppm): 7.89 (dd, 1H, J = 3.0, 1.0 Hz), 7.56 (dd, 1H, J = 5.0, 1.0 Hz), 7.33–7.37 (m, 3H), 7.10 (dd, 1H, J = 8.6, 2.6 Hz), 6.94 (d, 2H, J = 8.6 Hz), 6.79 (d, 2H, J = 8.6 Hz), 4.16 (t, 2H, J = 6.6 Hz), 3.83 (s, 2H), 3.21 (s, 3H), 2.96 (t, 2H, J = 6.6 Hz), 2.35 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H25Cl2N3O5S + Na]+, 596.0784 found, 596.0765/597.0942/598.0820.
Chinese Chemical Letters 19 (2008) 166–168 www.elsevier.com/locate/cclet
Synthesis of urea acetates as potential PPARa/g dual agonists Chang Yan Zhao a,b, Chang Qing Shi a,b, Yuan Wei Chen a,* a
Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China b Graduate School of Chinese Academy of Sciences, Beijing 100049, China Received 28 September 2007
Abstract In the quest for novel PPARa/g dual agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we designed and synthesized a series of urea acetates as potential PPARa/g dual agonists. The structure of the target compounds, intermediates were characterized by 1H NMR, HRMS. # 2007 Yuan Wei Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Oxazole; PPAR agonist; Type 2 diabetes; Urea; Ammonolysis; Synthesis
The nuclear receptor peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity and diabetes [1]. There are three PPAR subtypes which designated PPARa, PPARg and PPARd. The fibrate class of hypolipidemic drugs act through PPARa [2] and the thiazolidinedione class of anti-diabetic agents act through PPARg [3]. Synchronized therapies which concurrently control diabetes and inhibit progression of cardiovascular complications may be a fascinating therapeutic option in the treatment of diabetes. Therefore, PPARa/g dual agonists are under development to prevent diabetic cardiovascular complications. A number of PPARa/g dual agonists have appeared in the literature [4] and some of them are currently in clinical development. The compounds of PPARa/g dual agonists have a few essential pharmacophore elements. These comprise of an acidic group linked to a central flat ring and a large lipophilic substructure [5]. In order to search for more potent PPARa/g dual agonists, to study the structure– activity relationship of them and eventually to develop anti-diabetic agents, a novel series of urea acetates were designed and synthesized as Scheme 1. The starting material thiophene 3-carboxamide condensated with ethyl 4-bromo-3-oxopentanoate to provide ethyl 2-(5-methyl-2-(thiophen-3-yl)oxazol-4-yl) acetate, which can be easily purified by column chromatography. Reduction of ester 2 by LiAlH4 in THF produced the corresponding alcohol in high yield. Subsequent mesylation of the alcohol provided the methylsulfonate 3 quantitively. The 4-(2-(5-methyl-2-(thio-phen-3-yl)oxazol-4-yl)ethoxy)benzahyde 4 was obtained by the coupling of methylsulf-onate 3 with 4-hydroxylbenzaldehyde in CH3CN in the presence of potassium carbonate. Then, aldehyde 5 reacted with glycine methyl ester hydrochloride and sodium cyanoboro hydride in methanol to afford amino ester 6 in 90% yields. With the compound 6 in hand, a series of
* Corresponding author. E-mail address: [email protected] (Y.W. Chen). 1001-8417/$ – see front matter # 2007 Yuan Wei Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2007.12.013
C.Y. Zhao et al. / Chinese Chemical Letters 19 (2008) 166–168
167
Scheme 1. Reagents and conditions: (a) ethyl 4-bromo-3-oxopentanoate, toluene, reflux, 4 h, 51%; (b) THF, LAH, 0 8C, 2 h, >90%; (c) MeSO2Cl, Et3N, CH2Cl2, 25 8C, 2 h, >98%; (d) 4-hydroxybenzaldehyde, K2CO3, CH3CN, 80 8C, 24 h, 95%; (e) glycine methyl ester hydrochloride, anhydrous MgSO4, methanol, 0 8C, 0.5 h; NaCNBH3, 70 8C, 8 h, 90%; (f) R–PhNHCH3, triphosgene, Et3N, CH3CN, 0–25 8C, 12 h, 20–60%; (g) LiOHH2O, THF/H2O (1:1), 25 8C, 3 h, >95%.
substituted N-methyl benzenamines were used for the synthesis ureido esters 7. N-Methylbenzenamines was carbonylated with triphosgene in the presence of triethyl-amine, followed by addition of amino esters 6 in situ to give the desired ureido esters 7. Ureido esters 7 were hydrolyzed to provide the target compound 8 quantitatively. In conclusion, we have synthesized a series of urea acetates 8 in good yields via oxazole formation, coupling reaction, carbonylation and hydrolysis. These compounds contain a wide range of substitution patterns and were fully characterized. Moreover, we used N-methyl benzenamines which react with amino ester 6 to provide urea esters 7, this successfully prevented the ammonolysis of ester 6 to produce amide, see Ref. [6]. Functional activity assay of these compounds are currently in progess. Acknowledgments The authors thank the 100 Talents program of Chinese Academy of Sciences, the Chengdu Institute of Organic Chemistry, and the Graduate School of the Chinese Academy of Sciences for financial support of this work. References [1] [2] [3] [4]
D.E. Moller, Nature 414 (2001) 821. P.J. Brown, et al. J. Med. Chem. 42 (1999) 3785. J.M. Lehmann, L.B. Moore, T.A. Simth-Oliver, W.O. Wilkison, T.M. Willson, S.A. Kliewer, J. Biol. Chem. 270 (1995) 12953. (a) B.R. Henke, J. Med. Chem. 47 (2004) 4118; (b) Y. Lu, et al. Bioorg. Med. Chem. Lett. 16 (2006) 915; (c) P.V. Devasthale, et al. Bioorg. Med. Chem. Lett. 17 (2007) 2312. [5] B. Kuhn, et al. Bioorg. Med. Chem. Lett. 16 (2006) 4016.
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C.Y. Zhao et al. / Chinese Chemical Letters 19 (2008) 166–168
[6] Ammonolysis of amino ester in carbonylation was observed in our experiments, and the reaction product is characterized as follows:
1H NMR (300 Hz, CDCl3) dppm): 7.59 (m, 2H), 7.34 (m, 2H), 7.16 (m, 2H), 6.83 (m, 2H), 4.55 (s, 2H), 3.87 (s, 2H), 0.99 (s, 9H), 0.20 (s, 6H).; (8a) 1H NMR (300 Hz,CDCl3, dppm): 7.85 (dd, 1H, J = 3.0, 1.2 Hz), 7.56 (dd, 1H, J = 5.0, 1.2 Hz), 7.33–7.36 (m, 1H), 7.14–7.20 (m, 2H), 6.88– 6.97 (m, 2H), 6.69–6.79 (m, 4H), 4.14 (t, 2H, J = 6.6Hz), 4.08 (s, 2H), 3.83 (s, 3H), 3.69 (s, 2H), 3.14 (s, 3H), 2.92 (t, 2H, J = 6.6 Hz), 2.33 (s, 3H); HRMS (ESI, m/z): Calcd for [C28H29N3O6S + Na]+, 558.1669 found, 558.168; (8b) 1H NMR(300 Hz,CDCl3, dppm): 7.87 (dd, 1H, J = 3.0, 1.2 Hz), 7.55 (dd, 1H, J = 5.0, 1.2 Hz), 7.32–7.36 (m, 3H), 7.20–7.29 (m, 2H), 7.10– 7.15 (m, 1H), 6.89 (d, 2H, J = 8.6 Hz), 6.76 (d, 2H, J = 8.6 Hz), 4.16 (t, 2H, J = 6.6 Hz), 4.15 (s, 2H), 3.75 (s, 2H), 3.24 (s, 3H), 2.94 (t, 2H, J = 6.6 Hz), 2.33 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H27N3O5S + Na]+, 528.1564 found, 528.1557; (8c) 1H NMR (300 Hz,CDCl3, dppm): 7.87 (dd, 1H, J = 3.0, 1.2 Hz), 7.56 (dd, 1H, J = 5.0, 1.2 Hz), 7.33–7.36 (m, 1H), 7.21–7.29 (m, 1H), 7.00– 7.03 (m, 2H), 6.92–6.97 (m, 2H), 6.76–6.79 (m, 3H), 4.10–4.17 (m, 4H), 3.79 (s, 2H), 3.22 (s, 3H), 2.95 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H26FN3O5S + Na]+, 546.1469 found, 546.1456; (8d) 1H NMR (300 Hz, CDCl3, dppm): 7.86 (dd, 1H, J = 3.0, 1.0 Hz), 7.56 (dd, 1H, J = 5.0, 1.0 Hz), 7.34–7.36 (m, 1H), 7.18–7.24 (m, 1H), 6.90 (d, 2H, J = 8.6 Hz), 6.74–6.79 (m, 4H), 6.67 (d, 1H, J = 7.9 Hz), 4.14–4.17 (m, 4H), 3.99 (q, 2H, J = 6.9 Hz), 3.78 (s, 2H), 3.25 (s, 3H), 2.94 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H), 1.37 (t, 3H, J = 6.9 Hz); HRMS (ESI, m/z): Calcd for [C29H31N3O6S + Na]+, 572.1826 found, 572.1837; (8e) 1H NMR (300 Hz,CDCl3, dppm): 7.88 (d, 1H, J = 2.7 Hz), 7.56 (dd, 1H, J = 5.0, 1.0 Hz), 7.33–7.41 (m, 3H), 7.11 (d, 2H, J = 8.6 Hz), 6.92 (d, 2H, J = 8.6 Hz), 6.77 (d, 2H, J = 8.6 Hz), 4.17 (s, 2H, J = 6.6 Hz), 4.15 (s, 2H), 3.77 (s, 2H), 3.20 (s, 3H), 2.96 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H26BrN3O5S + Na]+, 606.0669 found, 606.0691/608.0672; (8f) 1H NMR (300 Hz, CDCl3, dppm): 7.87 (dd, 1H, J = 3.0, 1.1 Hz), 7.56 (dd, 1H, J = 5.0, 1.1 Hz), 7.34–7.37 (m, 1H), 7.26–7.29 (m, 2H), 7.14– 7.18 (m, 2H), 6.90 (d, 2H, J = 8.6 Hz), 6.77 (d, 2H, J = 8.6 Hz), 4.16 (s, 2H, J = 6.6 Hz), 4.13 (s, 2H), 3.79 (s, 2H), 3.21 (s, 3H), 2.95 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H26ClN3O5S + Na]+, 562.1174 found, 562.1163; (8g) 1H NMR (300 Hz,CDCl3, dppm): 7.86 (dd, 1H, J = 3.0, 1.1 Hz), 7.56 (dd, 1H, J = 5.0, 1.1 Hz), 7.34–7.35 (m, 1H), 7.07–7.14 (m, 4H), 6.86 (d, 2H, J = 8.6 Hz), 6.75 (d, 2H, J = 8.6 Hz), 4.16 (t, 2H, J = 6.6 Hz), 4.08 (s, 2H), 3.74 (s, 2H), 3.23 (s, 3H), 2.93 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H), 2.28 (s, 3H); HRMS (ESI, m/z): Calcd for C28H29N3O5S, 542.1720 found, 542.1735. HRMS (ESI, m/z): Calcd for [C28H29N3O5S + Na]+, 542.1720 found, 542.1735; (8h) 1H NMR (300 Hz,CDCl3, ppm): d 7.87 (dd, 1H, J = 3.0, 1.1 Hz), 7.56 (dd, 1H, J = 5.0, 1.1 Hz), 7.34–7.37 (m, 1H), 7.17–7.22 (m, 2H), 7.00 (t, 2H, J = 8.0 Hz), 6.90 (d, 2H, J = 8.6 Hz), 6.75–6.78 (m, 2H), 4.16 (t, 2H, J = 6.6 Hz), 4.10 (s, 2H), 3.76 (s, 2H), 3.20 (s, 3H), 2.95 (t, 2H, J = 6.6 Hz), 2.34 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H26FN3O5S + Na]+, 546.1469 found, 546.1456; (8i) 1H NMR (300 Hz,CDCl3, dppm): 7.89 (dd, 1H, J = 3.0, 1.1 Hz), 7.55–7.59 (m, 2H), 7.34–7.38 (m, 3H), 6.92 (d, 2H, J = 8.6 Hz), 6.78 (d, 2H, J = 8.6 Hz), 4.08–4.18 (m, 4H), 3.85 (s, 2H), 3.23 (s, 3H), 2.96 (t, 2H, J = 6.6 Hz), 2.35 (s, 3H); HRMS (ESI, m/z): Calcd for [C28H25ClF3N3O6S + Na]+, 630.1048 found, 630.1048/632.1014; (8j) 1H NMR (300 Hz,CDCl3, dppm): 7.88 (dd, 1H, J = 3.0, 1.1 Hz), 7.56 (dd, 1H, J = 5.0, 1.1 Hz), 7.34–7.37 (m, 1H), 7.21–7.26 (m, 2H), 7.06– 7.14 (m, 2H), 6.92 (d, 2H, J = 8.6 Hz), 6.78 (d, 2H, J = 8.6 Hz), 4.08–4.18 (m, 4H), 3.08 (s, 2H), 3.24 (s, 3H), 2.95 (t, 2H, J = 6.6Hz), 2.34 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H26ClN3O5S + Na]+, 562.1174 found, 562.1163; (8k) 1H NMR (300 Hz,CDCl3, dppm): 7.89 (dd, 1H, J = 3.0, 1.0 Hz), 7.56 (dd, 1H, J = 5.0, 1.0 Hz), 7.33–7.37 (m, 3H), 7.10 (dd, 1H, J = 8.6, 2.6 Hz), 6.94 (d, 2H, J = 8.6 Hz), 6.79 (d, 2H, J = 8.6 Hz), 4.16 (t, 2H, J = 6.6 Hz), 3.83 (s, 2H), 3.21 (s, 3H), 2.96 (t, 2H, J = 6.6 Hz), 2.35 (s, 3H); HRMS (ESI, m/z): Calcd for [C27H25Cl2N3O5S + Na]+, 596.0784 found, 596.0765/597.0942/598.0820.