Design, Synthesis and Biological Evaluation of Thrombin Inhibitors with 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine Nucleus†

doi:10.7503/cjcu20160797

Abstract

Abstract:

Compound 1, a new thrombin inhibitor with 1,2,3,4-tetrahydrobenzo[4,5] imidazo[1,2-a]pyrazine nucleus, was selected as lead compound, and fourteen carbamate derivatives derivatives(2a—6a, 2b—6b, 7—10) were designed and prepared. Furthermore, a twin drug(11) was synthesized by coupling compound 1 with 2-hydroxymethyl-3,5,6-trimethylpyrazine(HTMP). The structures of all the target compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. Preliminary biological activity test results indicated that all of the tested compounds exhibit a certain degree of inhibitory effect on thrombin-induced platelet aggregation, among which compound 4b[IC₅₀=(0.11±0.08) μmol/L] show better anti-platelet aggregation activity than dabigatran etexilate[IC₅₀=(0.60±0.05) μmol/L]. The in vivo experimental results in rat venous thrombosis model demonstrated compound 4b can significantly reduce thrombosis in a dose-response manner. Compound 11, which showed weak inhibitory effect on thrombin-induced platelet aggregation, also displayed comparable inhibitory effect on rat venous thrombosis with dabigatran etexilate. The study points out that the enhanced potency of compound 11 may be the synergetic effect of HTMP and compound 1 which are generated by hydrolysis in vivo.

Key words: Benzimidazole, Thrombin inhibitors, Antithrombosis

CLC Number:

O626

TrendMD:

CHEN Dongxing, SHI Jinyu, CHEN Qiufang, ZHANG Rui, GONG Guoqing, XU Yungen, ZHU Qihua. Design, Synthesis and Biological Evaluation of Thrombin Inhibitors with 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine Nucleus^†[J]. Chem. J. Chinese Universities, 2017, 38(6): 1059.

Figures/Tables 8

References 20

[1]	Fu Y., Wang D.W., Chinese J. Clin., 2006, 34(8), 51—53
	(付研, 王大为. 中国临床医生, 2006, 34(8), 51—53)
[2]	Mackman N., Becker R.C., Arterioscler. Thromb. Vasc. Biol., 2010, 30(3), 369—371
[3]	Rupin A., Marx I., Vallez M.O., Mennecier P., Gloanec P., de Nanteuil G., Verbeuren T. J., J. Thromb. Haemost., 2011, 9(7), 1375—1382
[4]	Xiao Z., Theroux P., Circulation, 1998, 97(3), 251—256
[5]	Ishibashi H., Koide M., Obara S., Kumasaka Y., Tamura K., J. Stroke. Cerebrovasc. Dis., 2013, 22(5), 656—660
[6]	Di Nisio M., Middeldorp S., Buller H.R., N. Engl. J. Med., 2005, 353(10), 1028—1040
[7]	Yang H.R., Ren Y. J., Gao X. D., Gao Y. H., Chem. Res. Chinese Universities, 2016, 32(6), 973—978
[8]	Connolly S.J., Ezekowitz M. D., Yusuf S., Eikelboom J., Oldgren J., Parekh A., Pogue J., Reilly P. A., Themeles E., Varrone J., Wang S., Alings M., Xavier D., Zhu J., Diaz R., Lewis B. S., Darius H., Diener H. C., Joyner C. D., Wallentin L., Engl. J. Med., 2009, 361(12), 1139—1151
[9]	Grave S., Aust. Nurs. J., 2011, 19(6), 30—33
[10]	Martins H.S., Scalabrini-Neto A., Velasco I. T., Lancet, 2007, 370(9604), 2002—2003
[11]	Hauel N.H., Nar H., Priepke H., Ries U., Stassen J. M., Wienen W., J. Med. Chem., 2002, 45(9), 1757—1766
[12]	Halton J.M., Lehr T., Cronin L., Lobmeyer M. T., Haertter S., Belletrutti M., Mitchell L. G., Thromb. Haemost., 2016, 116(3), 461—471
[13]	Imberti D., Pomero F., Benedetti R., Fenoglio L., Intern. Emerg. Med., 2016, 11(7), 895—900
[14]	Yang X.Z., Yang W. H., Xu Y. G., Diao X. J., He G. W., Gong G. Q., Eur. J. Med. Chem., 2012, 57, 21—28
[15]	Yang X.Z., Diao X. J., Yang W. H., Li F., He G. W., Gong G. Q., Xu Y. G., Bioorg. Med. Chem. Lett., 2013, 23(7), 2089—2092
[16]	Wang S.C., Dai P., Xu Y. G., Chen Q. F., Zhu Q. H., Gong G. Q., Arch. Pharm., 2015, 348(8), 595—605
[17]	Chen D.X., Wang S. C., Diao X. J., Zhu Q. H., Shen H. L., Han X. Q., Wang Y. W., Gong G. Q., Xu Y. G., Bioorg. Med. Chem., 2015, 23(23), 7405—7416
[18]	Li M., Handa S., Ikeda Y., Goto S., Thromb. Res., 2001, 104(1), 15—28
[19]	Liu J.B., Li Y. X., Chen Y. W., Wu C. C., Wan Y. Y., Wei W., Xiong L. X., Zhang X., Yu S. J., Li Z. M., Chem. Res. Chinese Universities, 2016, 32(1), 41—48
[20]	Jia C.Q., Yang D. Y., Che C. L., Ma Y. Q., Rui C. H., Yan X. J., Qin Z. H., Chem. J. Chinese Universities, 2016, 37(5), 892—901
	(贾长青, 杨冬燕, 车传亮, 马永强, 芮昌辉, 闫晓静, 覃兆海. 高等学校化学学报, 2016, 37(5), 892—901)

Compd.	Appearance	Yield(%)	m. p./℃	HRMS(calcd. ), m/z[M+H]⁺
2a	White solid	44.2	114—116	597.2823(597.2820)
2b	White solid	48.3	106—108	669.3044(669.3031)
3a	White solid	40.3	108—110	625.3148(625.3133)
3b	White solid	44.6	94—96	725.3673(725.3657)
4a	White solid	48.0	160—162	625.3141(625.3133)
4b	White solid	66.0	148—150	725.3662(725.3657)
5a	White solid	42.6	108—110	639.3287(639.3289)
5b	White solid	47.4	88—90	753.3978(753.3970)
6a	White solid	43.7	130—132	659.2979(659.2976)
6b	White solid	54.3	120—122	793.3354(793.3344)
7	White solid	29.9	> 250	511.2453(511.2452)
8	White solid	57.4	112—114	639.3295(639.3289)
9	White solid	59.6	82—84	667.3603(667.3602)
10	White solid	54.5	94—96	673.3145(673.3133)
11	Yellow solid	35.7	104—106	703.3356(703.3351)

Compd.	Appearance	Yield(%)	m. p./℃	HRMS(calcd. ), m/z[M+H]⁺
2a	White solid	44.2	114—116	597.2823(597.2820)
2b	White solid	48.3	106—108	669.3044(669.3031)
3a	White solid	40.3	108—110	625.3148(625.3133)
3b	White solid	44.6	94—96	725.3673(725.3657)
4a	White solid	48.0	160—162	625.3141(625.3133)
4b	White solid	66.0	148—150	725.3662(725.3657)
5a	White solid	42.6	108—110	639.3287(639.3289)
5b	White solid	47.4	88—90	753.3978(753.3970)
6a	White solid	43.7	130—132	659.2979(659.2976)
6b	White solid	54.3	120—122	793.3354(793.3344)
7	White solid	29.9	> 250	511.2453(511.2452)
8	White solid	57.4	112—114	639.3295(639.3289)
9	White solid	59.6	82—84	667.3603(667.3602)
10	White solid	54.5	94—96	673.3145(673.3133)
11	Yellow solid	35.7	104—106	703.3356(703.3351)

Compd.	¹H NMR(300 MHz), δ^a	¹³C NMR(75 MHz), δ^b
2a	9.14(brs, 2H), 7.87(d, J=8.3 Hz, 2H), 7.43(s, 1H), 7.38(d, J=8.3 Hz, 2H), 7.32—7.21(m, 2H), 7.21—7.06(m, 5H), 4.34—4.24(m, 1H), 4.15—3.99(m, 5H), 3.96(q, J=7.2 Hz, 2H), 3.91—3.81(m, 1H), 3.57—3.45(m, 1H), 3.29—3.20(m, 1H), 3.07—2.84(m, 2H), 2.58(t, J=7.1 Hz, 2H), 1.18(t, J=6.9 Hz, 3H), 1.11(t, J=7.1 Hz, 3H)	171.08, 170.63, 167.19, 163.87, 152.30, 142.83, 141.49, 140.86, 134.73, 132.51, 129.67, 129.05(2C), 128.78(2C), 127.33(2C), 127.28(2C), 126.19, 122.90, 119.95, 107.88, 60.78, 60.07, 55.29, 46.34, 42.50, 40.98, 38.95, 32.10, 13.93, 13.61
2b	9.59(brs, 2H), 7.85—7.59(m, 3H), 7.26—7.02(m, 9H), 5.89—5.63(m, 1H), 4.65—4.44(m, 1H), 4.41—3.80(m, 11H), 3.62—3.27(m, 2H), 2.76(t, J=7.2 Hz, 2H), 1.36(t, J=6.8 Hz, 3H), 1.32—1.18(m, 6H)	171.12, 170.38, 166.89, 164.02, 154.40, 150.11, 142.91, 141.21, 141.00, 134.20, 132.49, 130.10, 129.33(2C), 128.79(2C), 127.36(2C), 126.94(2C), 126.21, 123.18, 120.30, 107.95, 61.68, 60.89, 60.08, 53.49, 46.34, 41.36, 38.73, 36.87, 32.12, 13.91(2C), 13.62
3a	9.07(brs, 2H), 7.89(d, J=8.0 Hz, 2H), 7.46(s, 1H), 7.40(d, J=8.2 Hz, 2H), 7.34—7.21(m, 3H), 7.21—7.18(m, 2H), 7.18—7.15(m, 1H), 7.15—7.10(m, 1H), 4.38—4.19(m, 1H), 4.11(t, J=7.0 Hz, 2H), 4.07—4.03(m, 1H), 3.99(q, J=7.1 Hz, 2H), 3.94—3.85(m, 1H), 3.81(d, J=6.6 Hz, 2H), 3.60—3.44(m, 1H), 3.31—3.20(m, 1H), 3.08—2.87(m, 2H), 2.61(t, J=7.1 Hz, 2H), 1.99—1.81(m, 1H), 1.14(t, J=7.1 Hz, 3H), 0.91(d, J=6.7 Hz, 6H)	171.12, 170.64, 167.26, 164.34, 152.41, 142.93, 141.48, 140.98, 134.80, 132.90, 129.69, 129.11(2C), 128.78(2C), 127.35(2C), 127.23(2C), 126.16, 122.92, 120.06, 107.83, 71.25, 60.07, 55.42, 46.36, 42.65, 41.11, 39.04, 32.13, 27.33, 18.77(2C), 13.62
3b	9.07(brs, 2H), 7.88(s, 2H), 7.51(s, 1H), 7.35(d, J=8.6 Hz, 1H), 7.31—7.27(m, 1H), 7.27—7.21(m, 3H), 7.21—7.18(m, 2H), 7.18—7.04(m, 2H), 5.69—5.38(m, 1H), 4.45—4.27(m, 1H), 4.24—4.15(m, 1H), 4.11(t, J=7.2 Hz, 2H), 3.99(q, J=7.1 Hz, 3H), 3.81(d, J=6.6 Hz, 2H), 3.76—3.66(m, 1H), 3.60—3.51(m, 1H), 3.49—3.39(m, 1H), 3.33—3.24(m, 2H), 2.61(t, J=7.1 Hz, 2H), 1.97—1.81(m, 1H), 1.63—1.45(m, 1H), 1.14(t, J=7.1 Hz, 3H), 0.91(d, J=6.6 Hz, 6H), 0.83(s, 3H), 0.68(s, 3H)	171.10, 170.36, 166.91, 164.15, 154.56, 150.06, 142.91, 141.22, 140.77, 134.20, 132.77, 130.10, 129.32(2C), 128.79(2C), 127.36(2C), 126.98(2C), 126.21, 123.16, 120.30, 107.96, 71.85, 71.30, 60.06, 53.58, 46.33, 41.31, 39.21, 37.24, 32.11, 27.30(2C), 18.75(2C), 18.50(2C), 13.62
4a	9.03(brs, 2H), 7.83(d, J=8.2 Hz, 2H), 7.43(s, 1H), 7.36(d, J=8.2 Hz, 2H), 7.31—7.19(m, 3H), 7.18—7.15(m, 2H), 7.15—7.08(m, 2H), 4.32—4.20(m, 1H), 4.08(t, J=7.1 Hz, 2H), 4.04—4.00(m, 1H), 3.96(q, J=7.1 Hz, 2H), 3.91—3.81(m, 1H), 3.56—3.45(m, 1H), 3.28—3.18(m, 1H), 3.04—2.86(m, 2H), 2.58(t, J=7.1 Hz, 2H), 1.42(s, 9H), 1.11(t, J=7.1 Hz, 3H)	171.20, 170.63, 166.66, 162.89, 152.33, 142.95, 141.35, 140.93, 134.78, 132.98, 129.68, 129.16(2C), 128.80(2C), 127.36(2C), 127.19(2C), 126.16, 123.00, 120.11, 107.85, 79.37, 60.10, 55.42, 46.37, 42.63, 41.12, 39.01, 32.09, 27.69(3C), 13.64
4b	9.05(brs, 2H), 7.94(d,J=5.6 Hz, 2H), 7.50(s, 1H), 7.39—7.10(m, 9H), 5.60—5.43(m, 1H), 4.44—4.28(m, 1H), 4.26—4.15(m, 1H), 4.11(t, J=6.7 Hz, 2H), 3.99(q, J=7.1 Hz, 2H), 3.94—3.83(m, 1H), 3.57—3.39(m, 1H), 3.30—3.20(m, 2H), 2.61(t, J=7.2 Hz, 2H), 1.45(s, 9H), 1.34—1.19(m, 3H), 1.14(t, J=7.1 Hz, 3H), 1.12—0.99(m, 6H)	171.13, 170.40, 166.19, 162.93, 153.23, 150.49, 142.94, 141.26, 140.97, 134.26, 132.62, 130.03, 129.38(2C), 128.81(2C), 127.37(2C), 126.96(2C), 126.21, 123.15, 120.26, 107.98, 80.74, 79.50, 60.07, 53.66, 46.35, 41.43, 39.11, 36.29, 32.12, 27.69(6C), 13.63
5a	9.18(brs, 2H), 7.89(d, J=8.3 Hz, 2H), 7.46(s, 1H), 7.40(d, J=8.3 Hz, 2H), 7.35—7.21(m, 3H), 7.21—7.15(m, 3H), 7.15—7.10(m, 1H), 4.32—4.21(m, 1H), 4.10(t, J=6.9 Hz, 2H), 4.07—3.94(m, 5H), 3.94—3.82(m, 1H), 3.59—3.47(m, 1H), 3.31—3.20(m, 1H), 3.06—2.88(m, 2H), 2.61(t, J=6.9 Hz, 2H), 1.67—1.54(m, 2H), 1.37—1.27(m, 4H), 1.14(t, J=7.1 Hz, 3H), 0.88(t, J=7.0 Hz, 3H)	171.18, 170.65, 167.21, 164.06, 152.19, 142.85, 141.48, 140.88, 134.74, 132.63, 129.69, 129.18(2C), 128.81(2C), 127.35(2C), 127.28(2C), 126.21, 122.99, 120.05, 107.90, 65.19, 60.13, 55.38, 46.36, 42.49, 41.09, 38.96, 32.07, 28.03, 27.57, 21.91, 13.64, 13.50
5b	9.13(brs, 2H), 7.90(s, 2H), 7.50(s, 1H), 7.39—7.28(m, 2H), 7.28—7.22(m, 3H), 7.22—7.07(m, 4H), 5.65—5.41(m, 1H), 4.46—4.29(m, 1H), 4.28—4.16(m, 1H), 4.11(t, J=6.7 Hz, 2H), 4.05—3.86(m, 5H), 3.76—3.61(m, 1H), 3.61—3.41(m, 2H),	171.16, 170.39, 166.71, 164.36, 154.57, 150.08, 142.97, 141.28, 140.90, 134.24, 132.77, 130.15, 129.37(2C), 128.82(2C), 127.39(2C), 126.93(2C), 126.22, 123.22, 120.37, 107.95, 65.94,
Compd.	¹H NMR(300 MHz), δ^a	¹³C NMR(75 MHz), δ^b
5b	3.32—3.22(m, 2H), 2.61(t, J=7.0 Hz, 2H), 1.68—1.52(m, 2H), 1.39—1.17(m, 8H), 1.14(t, J=7.1 Hz, 3H), 1.11—0.95(m, 2H), 0.95—0.72(m, 6H)	65.18, 60.10, 53.61, 46.37, 41.37, 39.24, 37.12, 32.16, 28.05, 27.97, 27.60, 27.49, 21.91, 21.79, 13.66, 13.48, 13.45
6a	9.06(brs, 2H), 7.90(d,J=7.9 Hz, 2H), 7.46(s, 1H), 7.44—7.36(m, 5H), 7.36—7.32(m, 1H), 7.33—7.27(m, 2H), 7.27—7.21(m, 2H), 7.21—7.10(m, 4H), 5.10(s, 2H), 4.33—4.22(m, 1H), 4.10(t, J=7.0 Hz, 2H), 4.06—4.03(m, 1H), 3.99(q, J=7.0 Hz, 2H), 3.94—3.80(m, 1H), 3.59—3.47(m, 1H), 3.31—3.20(m, 1H), 3.09—2.82(m, 2H), 2.61(t, J=7.0 Hz, 2H), 1.14(t, J=7.1 Hz, 3H)	171.13, 170.64, 167.43, 163.97, 152.34, 142.95, 141.67, 140.96, 136.18, 134.78, 132.67, 129.74, 129.17(2C), 128.79(2C), 127.88(2C), 127.67(2C), 127.42, 127.36(2C), 127.23(2C), 126.16, 122.96, 120.08, 107.84, 66.66, 60.08, 55.38, 46.38, 42.61, 41.08, 39.05, 32.13, 13.64
6b	9.15(brs, 2H), 7.87(d, J=8.3 Hz, 2H), 7.50(s, 1H), 7.44—6.97(m, 19H), 5.69—5.47(m, 1H), 5.12(s, 2H), 4.97(s, 2H), 4.70—4.56(m, 1H), 4.42—4.24(m, 1H), 4.23—4.15(m, 1H), 4.11(t, J=6.8 Hz, 2H), 3.99(q, J=7.1 Hz, 2H), 3.68—3.37(m, 2H), 3.29—3.11(m, 1H), 2.61(t, J=7.2 Hz, 2H), 1.14(t, J=7.1 Hz, 3H)	171.14, 170.36, 166.19, 162.93, 153.23, 149.93, 142.92, 141.22, 140.83, 136.15, 135.79, 134.18, 132.52, 130.16, 129.30(2C), 128.80(2C), 128.03(2C), 127.89(2C), 127.69(2C), 127.63(2C), 127.59, 127.44, 127.37(2C), 126.96(2C), 126.22, 123.22, 120.33, 107.97, 66.70, 66.37, 60.09, 53.73, 46.35, 41.33, 39.19, 37.16, 32.14, 13.64
7	9.40(s, 2H), 9.20(s, 2H), 7.81(d,J=7.7 Hz, 2H), 7.62(d, J=7.9 Hz, 2H), 7.58—7.43(m, 2H), 7.32—7.24(m, 2H), 7.24—7.19(m, 2H), 7.19—7.15(m, 1H), 7.15—7.10(m, 1H), 5.11(brs, 1H), 4.42(brs, 2H), 4.10—3.99(m, 2H), 3.66(brs, 2H), 3.49(brs, 2H), 2.77(s, 3H), 2.60—2.52(m, 2H)	172.53, 169.36, 165.24, 148.40, 143.25, 143.03, 140.55, 133.80, 131.25, 129.87(2C), 129.23(2C), 128.10(2C), 127.99(2C), 126.74, 126.22, 123.82, 118.56, 110.43, 60.70, 49.68, 46.27, 38.45, 37.94, 37.90, 32.10
8	9.05(brs, 2H), 7.70(d, J=8.2 Hz, 2H), 7.47(s, 1H), 7.33—7.14(m, 9H), 4.16—4.12(m, 1H), 4.10(t, J=7.1 Hz, 2H), 4.06—4.03(m, 1H), 3.99(q, J=7.1 Hz, 2H), 3.92—3.77(m, 1H), 3.39—3.37(m, 1H),3.28—3.15(m, 2H), 2.92—2.77(m, 1H), 2.61(t, J=6.9 Hz, 2H), 2.40(s, 3H), 1.44(d, J=4.8 Hz, 9H), 1.14(t, J=7.1 Hz, 3H)	171.18, 170.63, 166.73, 160.39, 152.10, 144.01, 142.89, 141.10, 134.40, 131.26, 129.62, 129.39(2C), 128.79(2C), 127.36(2C), 126.47(2C), 126.19, 122.80, 119.94, 107.84, 79.78, 62.11, 60.09, 48.88, 46.35, 41.98, 39.94, 36.84, 32.09, 27.64(3C), 13.64
9	8.94(brs, 2H), 7.74(d, J=8.3 Hz, 2H), 7.47(s, 1H), 7.37—7.00(m, 9H), 4.17—4.05(m, 3H), 4.06—3.92(m, 5H), 3.91—3.75(m, 1H), 3.55(d, J=27.6 Hz, 1H), 3.27—3.13(m, 2H), 2.94—2.75(m, 1H), 2.61(t, J=6.8 Hz, 2H), 2.40(s, 3H),1.68—1.49(m, 2H), 1.36—1.25(m, 6H), 1.14(t, J=7.1 Hz, 3H), 0.86(t, J=6.6 Hz, 3H)	171.18, 170.58, 167.28, 161.05, 152.07, 142.97, 142.29, 141.20, 134.47, 131.79, 129.62, 129.38(2C), 128.78(2C), 127.35(2C), 126.43(2C), 126.13, 122.81, 120.06, 107.80, 65.14, 62.15, 60.08, 48.88, 46.35, 41.95, 39.84, 36.91, 32.09, 31.04, 28.30, 25.13, 22.07, 13.65, 13.55
10	9.15(brs, 2H), 7.89(d, J=8.2 Hz, 2H), 7.53—7.35(m, 4H), 7.35—7.28(m, 1H), 7.29—7.22(m, 3H), 7.22—7.17(m, 3H), 7.17—7.14(m, 2H), 7.15—7.05(m, 2H), 5.13(s, 2H), 4.34—4.23(m, 1H), 4.12(t, J=6.7 Hz, 2H), 4.08—4.04(m, 1H), 4.01(t, J=6.7 Hz, 2H), 3.94—3.85(m, 1H), 3.57—3.49(m, 2H), 3.06—2.90(m, 2H), 2.69(t, J=7.2 Hz, 2H), 2.42(s, 3H), 0.87(t, J=6.5 Hz, 3H)	171.18, 170.81, 167.63, 164.43, 152.41, 142.94, 141.60, 141.19, 137.74, 134.89, 132.95, 129.62, 129.43(2C), 128.83(2C), 127.87(2C), 127.67(2C), 127.37(2C), 127.23, 126.46(2C), 126.19, 123.10, 120.06, 107.88, 64.69, 61.82, 60.11, 48.82, 46.30, 41.93, 40.76, 37.08, 31.05, 13.56
11	9.55(brs, 2H), 7.81(d,J=7.9 Hz, 2H), 7.72(s, 1H), 7.34(d, J=8.4 Hz, 2H), 7.31(d, J=1.3 Hz, 1H), 7.25—7.18(m, 2H), 7.16—7.05(m, 4H), 5.30(s, 2H), 4.47—4.35(m, 1H), 4.34—4.22(m, 2H), 4.09(q, J=7.3 Hz, 2H), 4.05—3.96(m, 2H), 3.80—3.71(m, 1H), 3.47—3.37(m, 1H), 3.22—3.05(m, 2H), 2.80—2.71(m, 2H), 2.60(s, 3H), 2.51(s, 3H), 2.49(s, 3H), 1.23(t, J=7.1 Hz, 3H)	171.09, 170.65, 167.46, 163.62, 152.37, 150.41, 148.61, 148.19, 144.86, 142.75, 141.48, 140.82, 134.72, 132.45, 129.59, 128.96(2C), 128.79(2C), 127.36(2C), 127.32(2C), 126.22, 122.87, 119.89, 107.92, 65.43, 60.09, 55.30, 46.32, 42.49, 40.99, 38.93, 32.06, 21.09, 20.81, 20.08, 13.61

Compd.	¹H NMR(300 MHz), δ^a	¹³C NMR(75 MHz), δ^b
2a	9.14(brs, 2H), 7.87(d, J=8.3 Hz, 2H), 7.43(s, 1H), 7.38(d, J=8.3 Hz, 2H), 7.32—7.21(m, 2H), 7.21—7.06(m, 5H), 4.34—4.24(m, 1H), 4.15—3.99(m, 5H), 3.96(q, J=7.2 Hz, 2H), 3.91—3.81(m, 1H), 3.57—3.45(m, 1H), 3.29—3.20(m, 1H), 3.07—2.84(m, 2H), 2.58(t, J=7.1 Hz, 2H), 1.18(t, J=6.9 Hz, 3H), 1.11(t, J=7.1 Hz, 3H)	171.08, 170.63, 167.19, 163.87, 152.30, 142.83, 141.49, 140.86, 134.73, 132.51, 129.67, 129.05(2C), 128.78(2C), 127.33(2C), 127.28(2C), 126.19, 122.90, 119.95, 107.88, 60.78, 60.07, 55.29, 46.34, 42.50, 40.98, 38.95, 32.10, 13.93, 13.61
2b	9.59(brs, 2H), 7.85—7.59(m, 3H), 7.26—7.02(m, 9H), 5.89—5.63(m, 1H), 4.65—4.44(m, 1H), 4.41—3.80(m, 11H), 3.62—3.27(m, 2H), 2.76(t, J=7.2 Hz, 2H), 1.36(t, J=6.8 Hz, 3H), 1.32—1.18(m, 6H)	171.12, 170.38, 166.89, 164.02, 154.40, 150.11, 142.91, 141.21, 141.00, 134.20, 132.49, 130.10, 129.33(2C), 128.79(2C), 127.36(2C), 126.94(2C), 126.21, 123.18, 120.30, 107.95, 61.68, 60.89, 60.08, 53.49, 46.34, 41.36, 38.73, 36.87, 32.12, 13.91(2C), 13.62
3a	9.07(brs, 2H), 7.89(d, J=8.0 Hz, 2H), 7.46(s, 1H), 7.40(d, J=8.2 Hz, 2H), 7.34—7.21(m, 3H), 7.21—7.18(m, 2H), 7.18—7.15(m, 1H), 7.15—7.10(m, 1H), 4.38—4.19(m, 1H), 4.11(t, J=7.0 Hz, 2H), 4.07—4.03(m, 1H), 3.99(q, J=7.1 Hz, 2H), 3.94—3.85(m, 1H), 3.81(d, J=6.6 Hz, 2H), 3.60—3.44(m, 1H), 3.31—3.20(m, 1H), 3.08—2.87(m, 2H), 2.61(t, J=7.1 Hz, 2H), 1.99—1.81(m, 1H), 1.14(t, J=7.1 Hz, 3H), 0.91(d, J=6.7 Hz, 6H)	171.12, 170.64, 167.26, 164.34, 152.41, 142.93, 141.48, 140.98, 134.80, 132.90, 129.69, 129.11(2C), 128.78(2C), 127.35(2C), 127.23(2C), 126.16, 122.92, 120.06, 107.83, 71.25, 60.07, 55.42, 46.36, 42.65, 41.11, 39.04, 32.13, 27.33, 18.77(2C), 13.62
3b	9.07(brs, 2H), 7.88(s, 2H), 7.51(s, 1H), 7.35(d, J=8.6 Hz, 1H), 7.31—7.27(m, 1H), 7.27—7.21(m, 3H), 7.21—7.18(m, 2H), 7.18—7.04(m, 2H), 5.69—5.38(m, 1H), 4.45—4.27(m, 1H), 4.24—4.15(m, 1H), 4.11(t, J=7.2 Hz, 2H), 3.99(q, J=7.1 Hz, 3H), 3.81(d, J=6.6 Hz, 2H), 3.76—3.66(m, 1H), 3.60—3.51(m, 1H), 3.49—3.39(m, 1H), 3.33—3.24(m, 2H), 2.61(t, J=7.1 Hz, 2H), 1.97—1.81(m, 1H), 1.63—1.45(m, 1H), 1.14(t, J=7.1 Hz, 3H), 0.91(d, J=6.6 Hz, 6H), 0.83(s, 3H), 0.68(s, 3H)	171.10, 170.36, 166.91, 164.15, 154.56, 150.06, 142.91, 141.22, 140.77, 134.20, 132.77, 130.10, 129.32(2C), 128.79(2C), 127.36(2C), 126.98(2C), 126.21, 123.16, 120.30, 107.96, 71.85, 71.30, 60.06, 53.58, 46.33, 41.31, 39.21, 37.24, 32.11, 27.30(2C), 18.75(2C), 18.50(2C), 13.62
4a	9.03(brs, 2H), 7.83(d, J=8.2 Hz, 2H), 7.43(s, 1H), 7.36(d, J=8.2 Hz, 2H), 7.31—7.19(m, 3H), 7.18—7.15(m, 2H), 7.15—7.08(m, 2H), 4.32—4.20(m, 1H), 4.08(t, J=7.1 Hz, 2H), 4.04—4.00(m, 1H), 3.96(q, J=7.1 Hz, 2H), 3.91—3.81(m, 1H), 3.56—3.45(m, 1H), 3.28—3.18(m, 1H), 3.04—2.86(m, 2H), 2.58(t, J=7.1 Hz, 2H), 1.42(s, 9H), 1.11(t, J=7.1 Hz, 3H)	171.20, 170.63, 166.66, 162.89, 152.33, 142.95, 141.35, 140.93, 134.78, 132.98, 129.68, 129.16(2C), 128.80(2C), 127.36(2C), 127.19(2C), 126.16, 123.00, 120.11, 107.85, 79.37, 60.10, 55.42, 46.37, 42.63, 41.12, 39.01, 32.09, 27.69(3C), 13.64
4b	9.05(brs, 2H), 7.94(d,J=5.6 Hz, 2H), 7.50(s, 1H), 7.39—7.10(m, 9H), 5.60—5.43(m, 1H), 4.44—4.28(m, 1H), 4.26—4.15(m, 1H), 4.11(t, J=6.7 Hz, 2H), 3.99(q, J=7.1 Hz, 2H), 3.94—3.83(m, 1H), 3.57—3.39(m, 1H), 3.30—3.20(m, 2H), 2.61(t, J=7.2 Hz, 2H), 1.45(s, 9H), 1.34—1.19(m, 3H), 1.14(t, J=7.1 Hz, 3H), 1.12—0.99(m, 6H)	171.13, 170.40, 166.19, 162.93, 153.23, 150.49, 142.94, 141.26, 140.97, 134.26, 132.62, 130.03, 129.38(2C), 128.81(2C), 127.37(2C), 126.96(2C), 126.21, 123.15, 120.26, 107.98, 80.74, 79.50, 60.07, 53.66, 46.35, 41.43, 39.11, 36.29, 32.12, 27.69(6C), 13.63
5a	9.18(brs, 2H), 7.89(d, J=8.3 Hz, 2H), 7.46(s, 1H), 7.40(d, J=8.3 Hz, 2H), 7.35—7.21(m, 3H), 7.21—7.15(m, 3H), 7.15—7.10(m, 1H), 4.32—4.21(m, 1H), 4.10(t, J=6.9 Hz, 2H), 4.07—3.94(m, 5H), 3.94—3.82(m, 1H), 3.59—3.47(m, 1H), 3.31—3.20(m, 1H), 3.06—2.88(m, 2H), 2.61(t, J=6.9 Hz, 2H), 1.67—1.54(m, 2H), 1.37—1.27(m, 4H), 1.14(t, J=7.1 Hz, 3H), 0.88(t, J=7.0 Hz, 3H)	171.18, 170.65, 167.21, 164.06, 152.19, 142.85, 141.48, 140.88, 134.74, 132.63, 129.69, 129.18(2C), 128.81(2C), 127.35(2C), 127.28(2C), 126.21, 122.99, 120.05, 107.90, 65.19, 60.13, 55.38, 46.36, 42.49, 41.09, 38.96, 32.07, 28.03, 27.57, 21.91, 13.64, 13.50
5b	9.13(brs, 2H), 7.90(s, 2H), 7.50(s, 1H), 7.39—7.28(m, 2H), 7.28—7.22(m, 3H), 7.22—7.07(m, 4H), 5.65—5.41(m, 1H), 4.46—4.29(m, 1H), 4.28—4.16(m, 1H), 4.11(t, J=6.7 Hz, 2H), 4.05—3.86(m, 5H), 3.76—3.61(m, 1H), 3.61—3.41(m, 2H),	171.16, 170.39, 166.71, 164.36, 154.57, 150.08, 142.97, 141.28, 140.90, 134.24, 132.77, 130.15, 129.37(2C), 128.82(2C), 127.39(2C), 126.93(2C), 126.22, 123.22, 120.37, 107.95, 65.94,
Compd.	¹H NMR(300 MHz), δ^a	¹³C NMR(75 MHz), δ^b
5b	3.32—3.22(m, 2H), 2.61(t, J=7.0 Hz, 2H), 1.68—1.52(m, 2H), 1.39—1.17(m, 8H), 1.14(t, J=7.1 Hz, 3H), 1.11—0.95(m, 2H), 0.95—0.72(m, 6H)	65.18, 60.10, 53.61, 46.37, 41.37, 39.24, 37.12, 32.16, 28.05, 27.97, 27.60, 27.49, 21.91, 21.79, 13.66, 13.48, 13.45
6a	9.06(brs, 2H), 7.90(d,J=7.9 Hz, 2H), 7.46(s, 1H), 7.44—7.36(m, 5H), 7.36—7.32(m, 1H), 7.33—7.27(m, 2H), 7.27—7.21(m, 2H), 7.21—7.10(m, 4H), 5.10(s, 2H), 4.33—4.22(m, 1H), 4.10(t, J=7.0 Hz, 2H), 4.06—4.03(m, 1H), 3.99(q, J=7.0 Hz, 2H), 3.94—3.80(m, 1H), 3.59—3.47(m, 1H), 3.31—3.20(m, 1H), 3.09—2.82(m, 2H), 2.61(t, J=7.0 Hz, 2H), 1.14(t, J=7.1 Hz, 3H)	171.13, 170.64, 167.43, 163.97, 152.34, 142.95, 141.67, 140.96, 136.18, 134.78, 132.67, 129.74, 129.17(2C), 128.79(2C), 127.88(2C), 127.67(2C), 127.42, 127.36(2C), 127.23(2C), 126.16, 122.96, 120.08, 107.84, 66.66, 60.08, 55.38, 46.38, 42.61, 41.08, 39.05, 32.13, 13.64
6b	9.15(brs, 2H), 7.87(d, J=8.3 Hz, 2H), 7.50(s, 1H), 7.44—6.97(m, 19H), 5.69—5.47(m, 1H), 5.12(s, 2H), 4.97(s, 2H), 4.70—4.56(m, 1H), 4.42—4.24(m, 1H), 4.23—4.15(m, 1H), 4.11(t, J=6.8 Hz, 2H), 3.99(q, J=7.1 Hz, 2H), 3.68—3.37(m, 2H), 3.29—3.11(m, 1H), 2.61(t, J=7.2 Hz, 2H), 1.14(t, J=7.1 Hz, 3H)	171.14, 170.36, 166.19, 162.93, 153.23, 149.93, 142.92, 141.22, 140.83, 136.15, 135.79, 134.18, 132.52, 130.16, 129.30(2C), 128.80(2C), 128.03(2C), 127.89(2C), 127.69(2C), 127.63(2C), 127.59, 127.44, 127.37(2C), 126.96(2C), 126.22, 123.22, 120.33, 107.97, 66.70, 66.37, 60.09, 53.73, 46.35, 41.33, 39.19, 37.16, 32.14, 13.64
7	9.40(s, 2H), 9.20(s, 2H), 7.81(d,J=7.7 Hz, 2H), 7.62(d, J=7.9 Hz, 2H), 7.58—7.43(m, 2H), 7.32—7.24(m, 2H), 7.24—7.19(m, 2H), 7.19—7.15(m, 1H), 7.15—7.10(m, 1H), 5.11(brs, 1H), 4.42(brs, 2H), 4.10—3.99(m, 2H), 3.66(brs, 2H), 3.49(brs, 2H), 2.77(s, 3H), 2.60—2.52(m, 2H)	172.53, 169.36, 165.24, 148.40, 143.25, 143.03, 140.55, 133.80, 131.25, 129.87(2C), 129.23(2C), 128.10(2C), 127.99(2C), 126.74, 126.22, 123.82, 118.56, 110.43, 60.70, 49.68, 46.27, 38.45, 37.94, 37.90, 32.10
8	9.05(brs, 2H), 7.70(d, J=8.2 Hz, 2H), 7.47(s, 1H), 7.33—7.14(m, 9H), 4.16—4.12(m, 1H), 4.10(t, J=7.1 Hz, 2H), 4.06—4.03(m, 1H), 3.99(q, J=7.1 Hz, 2H), 3.92—3.77(m, 1H), 3.39—3.37(m, 1H),3.28—3.15(m, 2H), 2.92—2.77(m, 1H), 2.61(t, J=6.9 Hz, 2H), 2.40(s, 3H), 1.44(d, J=4.8 Hz, 9H), 1.14(t, J=7.1 Hz, 3H)	171.18, 170.63, 166.73, 160.39, 152.10, 144.01, 142.89, 141.10, 134.40, 131.26, 129.62, 129.39(2C), 128.79(2C), 127.36(2C), 126.47(2C), 126.19, 122.80, 119.94, 107.84, 79.78, 62.11, 60.09, 48.88, 46.35, 41.98, 39.94, 36.84, 32.09, 27.64(3C), 13.64
9	8.94(brs, 2H), 7.74(d, J=8.3 Hz, 2H), 7.47(s, 1H), 7.37—7.00(m, 9H), 4.17—4.05(m, 3H), 4.06—3.92(m, 5H), 3.91—3.75(m, 1H), 3.55(d, J=27.6 Hz, 1H), 3.27—3.13(m, 2H), 2.94—2.75(m, 1H), 2.61(t, J=6.8 Hz, 2H), 2.40(s, 3H),1.68—1.49(m, 2H), 1.36—1.25(m, 6H), 1.14(t, J=7.1 Hz, 3H), 0.86(t, J=6.6 Hz, 3H)	171.18, 170.58, 167.28, 161.05, 152.07, 142.97, 142.29, 141.20, 134.47, 131.79, 129.62, 129.38(2C), 128.78(2C), 127.35(2C), 126.43(2C), 126.13, 122.81, 120.06, 107.80, 65.14, 62.15, 60.08, 48.88, 46.35, 41.95, 39.84, 36.91, 32.09, 31.04, 28.30, 25.13, 22.07, 13.65, 13.55
10	9.15(brs, 2H), 7.89(d, J=8.2 Hz, 2H), 7.53—7.35(m, 4H), 7.35—7.28(m, 1H), 7.29—7.22(m, 3H), 7.22—7.17(m, 3H), 7.17—7.14(m, 2H), 7.15—7.05(m, 2H), 5.13(s, 2H), 4.34—4.23(m, 1H), 4.12(t, J=6.7 Hz, 2H), 4.08—4.04(m, 1H), 4.01(t, J=6.7 Hz, 2H), 3.94—3.85(m, 1H), 3.57—3.49(m, 2H), 3.06—2.90(m, 2H), 2.69(t, J=7.2 Hz, 2H), 2.42(s, 3H), 0.87(t, J=6.5 Hz, 3H)	171.18, 170.81, 167.63, 164.43, 152.41, 142.94, 141.60, 141.19, 137.74, 134.89, 132.95, 129.62, 129.43(2C), 128.83(2C), 127.87(2C), 127.67(2C), 127.37(2C), 127.23, 126.46(2C), 126.19, 123.10, 120.06, 107.88, 64.69, 61.82, 60.11, 48.82, 46.30, 41.93, 40.76, 37.08, 31.05, 13.56
11	9.55(brs, 2H), 7.81(d,J=7.9 Hz, 2H), 7.72(s, 1H), 7.34(d, J=8.4 Hz, 2H), 7.31(d, J=1.3 Hz, 1H), 7.25—7.18(m, 2H), 7.16—7.05(m, 4H), 5.30(s, 2H), 4.47—4.35(m, 1H), 4.34—4.22(m, 2H), 4.09(q, J=7.3 Hz, 2H), 4.05—3.96(m, 2H), 3.80—3.71(m, 1H), 3.47—3.37(m, 1H), 3.22—3.05(m, 2H), 2.80—2.71(m, 2H), 2.60(s, 3H), 2.51(s, 3H), 2.49(s, 3H), 1.23(t, J=7.1 Hz, 3H)	171.09, 170.65, 167.46, 163.62, 152.37, 150.41, 148.61, 148.19, 144.86, 142.75, 141.48, 140.82, 134.72, 132.45, 129.59, 128.96(2C), 128.79(2C), 127.36(2C), 127.32(2C), 126.22, 122.87, 119.89, 107.92, 65.43, 60.09, 55.30, 46.32, 42.49, 40.99, 38.93, 32.06, 21.09, 20.81, 20.08, 13.61