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4037
J = 8.7 Hz, 2H), 5.28 (d, J = 6.9 Hz, 1H) 4.35 (s, 2H), 3.97 (m, 1H),
3.88–3.12 (m, 7H), 2.64–2.20 (m, 3H), 2.06–1.42 (m, 8H),
1.40–1.00 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H), 0.80 (m, 2H); MS
(MALDI, Pos) m/z 578 (M+H)+; HRMS Calcd 578.3230, Obsd
578.3228.
5.1.2.18. 4-[4-({(3R)-1-Butyl-3-[(R)-hydroxy(tetrahydro-2H-pyr
an-4-yl)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-
yl}methyl)phenoxy]benzoic acid hydrochloride (19). TLC Rf
0.30 (CHCl3/MeOH, 4/1); 1H NMR (300 MHz, CD3OD) d 8.04 (d,
J = 9.0 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H),
7.07 (d, J = 9.0 Hz, 2H), 4.37 (s, 2H), 4.12 (d, J = 2.0 Hz, 1H), 4.08–
3.93 (m, 3H), 3.75 (m, 1H), 3.57–3.34 (m, 5H), 3.30–3.15 (m, 2H),
2.52–1.69 (m, 8H), 1.50–1.18 (m, 5H), 0.96 (t, J = 7.2 Hz, 3H); MS
(APCI, Pos 20v) m/z 580 (M+H)+; HRMS Calcd 580.3023, Obsd
580.3016.
5.1.2.13.
pyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phen-
oxy]benzoic acid hydrochloride (14). +10.08° (c 1.07,
4-[4-({(3R)-1-Butyl-3-[(1R)-1-hydroxy-2-methylpro-
½ ꢂ
a 2D6
MeOH) TLC Rf 0.32 (AcOEt/MeOH, 2/1); 1H NMR (300 MHz, CD3OD)
d 8.04 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz,
2H), 7.07 (d, J = 8.7 Hz, 2H), 4.37 (s, 2H), 4.15 (d, J = 2.4 Hz, 1H),
4.02 (m, 1H), 3.76 (m, 1H), 3.60–3.44 (m, 3H), 3.24–3.08 (m, 2H),
2.56–1.92 (m, 5H), 1.70 (m, 1H), 1.50–1.26 (m, 3H), 1.08–0.90
(m, 9H); IR (KBr) 2962, 1675, 1599, 1504, 1422, 1245,
1162 cmꢁ1; MS (APCI, Pos 20v) m/z 538 (M+H)+; HRMS Calcd
538.2917, Obsd 538.2925.
5.1.2.19. 4-[4-({(3R)-1-Butyl-3-[(R)-hydroxy(4-hydroxycyclohexyl)
methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)
phenoxy]benzoic acid hydrochloride (20a). TLC Rf 0.17 (AcOEt/
MeOH, 2/1); 1H NMR (300 MHz, CD3OD) d 8.02 (d, J = 8.7 Hz, 2H),
7.59 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.7 Hz,
2H), 4.32 (s, 2H), 4.17 (d, J = 1.8 Hz, 1H), 4.00–3.91 (m, 2H), 3.70
(m, 1H), 3.52–3.37 (m, 3H), 3.30–3.17 (m, 2H), 2.50–2.33 (m,
3H), 2.10 (m, 1H), 1.80–1.18 (m, 12H), 0.94 (t, J = 7.0 Hz, 3H); IR
(KBr) 2934, 1672, 1598, 1502, 1422, 1243, 1161, 1112 cmꢁ1; MS
(APCI, Pos 20v) m/z 594 (M+H)+; HRMS Calcd 594.3179, Obsd
594.3176.
5.1.2.14. 4-[4-({(3R)-1-Butyl-3-[(R)-cyclopropyl(hydroxy)methyl
]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phen-
oxy]benzoic acid hydrochloride (15). TLC Rf 0.29 (AcOEt/MeOH,
2/1); 1H NMR (300 MHz, CD3OD) d 8.03 (d, J = 9.0 Hz, 2H), 7.64 (d,
J = 9.0 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 4.37
(s, 2H), 4.11 (d, J = 2.5 Hz, 1H), 3.92 (m, 1H), 3.80 (m, 1H), 3.54–
3.34 (m, 4H), 3.14 (dd, J = 9.0, 2.5 Hz, 1H), 2.61–2.43 (m, 2H),
2.35 (m, 1H), 2.15 (m, 1H), 1.70–1.49 (m, 2H), 1.49–1.33 (m, 2H),
1.09 (m, 1H), 0.96 (t, J = 7.5 Hz, 3H), 0.60–0.43 (m, 2H), 0.33 (m,
1H), 0.24 (m, 1H); IR (KBr) 3219, 2958, 2873, 2582, 1710, 1672,
1598, 1502, 1422, 1385, 1243, 1161, 1113, 1098, 1049 cmꢁ1; MS
(APCI, Neg 20v) m/z 534 (MꢁH)ꢁ; HRMS Calcd 536.2761, Obsd
536.2757.
5.1.2.20. 4-[4-({(3R)-1-Butyl-3-[(R)-hydroxy(4-hydroxycyclohex
yl)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-
yl}methyl)phenoxy]benzoic acid hydrochloride (20b). TLC Rf
0.27 (CH2Cl2/MeOH, 3/1); 1H NMR (300 MHz, CD3OD) d 8.03 (d,
J = 8.9 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H),
7.07 (d, J = 8.9 Hz, 2H), 4.36 (s, 2H), 4.14 (d, J = 2.1 Hz, 1H), 3.97
(m, 1H), 3.71 (m, 1H), 3.57–3.41 (m, 4H), 3.30–3.24 (m, 2H),
2.58–2.43 (m, 3H), 2.12–1.68 (m, 6H), 1.40–0.93 (m, 8H), 0.95 (t,
J = 7.0 Hz, 3H); IR (KBr) 2934, 1676, 1599, 1502, 1423, 1243,
1161, 1098, 1048 cmꢁ1; MS (APCI, Neg 20v) m/z 592 (MꢁH)ꢁ;
HRMS Calcd 594.3179, Obsd 594.3185.
5.1.2.15. 4-[4-({(3R)-1-Butyl-3-[(R)-cyclobutyl(hydroxy)methyl
]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phen-
oxy]benzoic acid hydrochloride (16). TLC Rf 0.68 (BuOH/AcOH/
H2O, 4/2/1); 1H NMR (300 MHz, CD3OD) d 8.02 (d, J = 8.5 Hz, 2H),
7.61 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz,
2H), 4.32 (s, 2H), 3.90 (m, 1H), 3.90 (d, J = 2.0 Hz, 1H), 3.73 (m,
1H), 3.68 (dd, J = 9.0, 2.0 Hz, 1H), 3.53–3.40 (m, 3H), 3.26
(m, 1H), 2.67 (m, 1H), 2.51 (m, 1H), 2.43–2.37 (m, 2H), 2.15–1.29
(m, 11H), 0.94 (t, J = 7.0 Hz, 3H); MS (APCI, Neg 20v) m/z 548
(M–H)ꢁ; HRMS Calcd 550.2917, Obsd 550.2924.
5.1.2.21. 4-[4-({(3R)-3-[Cyclohexyl(hydroxy)methyl]-1-methyl-
2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phen-
oxy]benzoic acid hydrochloride (21). TLC Rf 0.55 (CH2Cl2/MeOH,
4/1); 1H NMR (300 MHz, CD3OD) d 8.03 (d, J = 8.7 Hz, 2H), 7.60 (d,
J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 4.38
(s, 2H), 4.17 (d, J = 1.8 Hz, 1H), 3.99 (m, 1H), 3.79 (m, 1H), 3.50–
3.46 (m, 2H), 3.26 (dd, J = 9.6, 1.8 Hz, 1H), 2.95 (s, 3H), 2.60–2.36
(m, 3H), 2.12–1.94 (m, 3H), 1.80–1.64 (m, 4H), 1.38–1.18 (m,
3H), 1.00–0.88 (m, 2H); IR (KBr) 3385, 2926, 2852, 1684, 1598,
1503, 1427, 1244, 1161 cmꢁ1
; MS (APCI, Pos 20v) m/z 536
5.1.2.16. 4-[4-({(3R)-1-Butyl-3-[(R)-cyclopentyl(hydroxy)methyl
]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phen-
oxy]benzoic acid hydrochloride (17). TLC Rf 0.45 (CHCl3/MeOH,
5/1); 1H NMR (300 MHz, CD3OD) d 8.05 (d, J = 8.7 Hz, 2H), 7.61
(d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H),
4.38 (s, 2H), 4.02 (m, 1H), 4.01 (d, J = 1.8 Hz, 1H), 3.78 (m, 1H),
3.62–3.08 (m, 5H), 2.60–2.06 (m, 5H), 2.00–1.08 (m, 12H), 0.96
(t, J = 6.9 Hz, 3H); IR (KBr) 3424, 2957, 2871, 2586, 1665, 1599,
1503, 1421, 1371, 1311, 1244, 1162, 1098, 1049 cmꢁ1; MS (FAB,
Pos, glycerin + m-NBA) m/z 564 (M+H)+; HRMS Calcd 564.3074,
Obsd 564.3074.
(M+H)+; HRMS Calcd 536.2761, Obsd 536.2762.
5.1.2.22. 4-[4-({(3R)-3-[Cyclohexyl(hydroxy)methyl]-1-ethyl-2,5
-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenoxy]ben-
zoic acid hydrochloride (23). TLC Rf 0.66 (CH2Cl2/MeOH, 4/1); 1H
NMR (300 MHz, CD3OD) d 8.03 (d, J = 9.0 Hz, 2H), 7.61 (d, J = 9.0 Hz,
2H), 7.17 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 4.37 (s, 2H),
4.15 (d, J = 2.0 Hz, 1H), 4.00 (m, 1H), 3.76 (m, 1H), 3.63 (m, 1H),
3.49–3.45 (m, 2H), 3.33–3.26 (m, 2H), 2.50–2.38 (m, 3H), 2.17–
1.93 (m, 3H), 1.80–1.65 (m, 4H), 1.34–1.17 (m, 6H), 1.00–0.87
(m, 2H); IR (KBr) 3049, 2924, 1703, 1677, 1649, 1599, 1502,
1422, 1248, 1167, 1113 cmꢁ1
; MS (APCI, Pos 20v) m/z 550
5.1.2.17. 4-[4-({(3R)-1-Butyl-3-[(R)-cycloheptyl(hydroxy)meth y
l]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phen-
oxy]benzoic acid hydrochloride (18). TLC Rf 0.28 (CH2Cl2/MeOH,
10/1); 1H NMR (300 MHz, CD3OD) d 8.03 (d, J = 9.0 Hz, 2H), 7.59 (d,
J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 4.37
(s, 2H), 4.15 (d, J = 2.4 Hz, 1H), 4.02 (m, 1H), 3.76 (m, 1H), 3.58–
3.44 (m, 3H), 3.30–3.07 (m, 2H), 2.51–1.17 (m, 21H), 0.96 (t,
J = 7.0 Hz, 3H); IR (KBr) 2930, 1672, 1599, 1502, 1420, 1244,
1161, 1115 cmꢁ1; MS (APCI, Neg 20v) m/z 590 (M–H)ꢁ; HRMS
Calcd 592.3387, Obsd 592.3383.
(M+H)+; HRMS Calcd 550.2917, Obsd 550.2922.
5.1.2.23. 4-[4-({(3R)-3-[(R)-Cyclohexyl(hydroxy)methyl]-2,5-di
oxo-1-propyl-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phen-
oxy]benzoic acid hydrochloride (25). TLC Rf 0.21 (CHCl3/MeOH/
AcOH, 20/2/1); 1H NMR (300 MHz, CD3OD) d 8.04 (d, J = 9.0 Hz, 2H),
7.62 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 9.0 Hz,
2H), 4.37 (s, 2H), 4.15 (d, J = 2.1 Hz, 1H), 4.01 (m, 1H), 3.75 (m,
1H), 3.55–3.38 (m, 3H), 3.30–3.09 (m, 2H), 2.55–2.26 (m, 3H),