G. Zhou et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2890–2893
2893
EtO
EtO
Cl
H
N
O
b
O
a
O2N
Cl
c
a, b
O2N
HO
c
NH2
NO2
NO2
COOMe
COOMe
O
O
O
OTf
S
Cl
Cl
Ph
N
N
N
N
Cl
15
12
13
14
SMe
SMe
26
24
23
25
Cl
Cl
d
EtO
Ph
d
EtO
Ph
O
O
NH
e
H2N
O
O
f
EtO
S
O
N
N
S
f, g
e
NBoc
O
N
NBoc
N
O
Ph
O
N
N
O
N
O
N
N
16
N
N
N
N
17
5
SMe
28
7
Cl
27
Cl
Cl
Scheme 1. Reagents and conditions: (a) tBuOH, KOH,
D, 10 h; (b) DEAD, Ph3P,
EtOCH2CH2OH, THF, rt, 12 h; (c) Bu3SnPh, Pd(Ph3P)2Cl2, dioxane, 80 °C, 18 h; (d) Fe,
2 N HCl in water, ethanol, 3.5 h; (e) (ClCH2CH2)2NH, K2CO3, diglyme, 180 °C, 72 h;
(f) RSO2Cl, Et3N, CH2Cl2, rt, 10 h.
Scheme 3. Reagents and conditions: (a) NaOMe, MeOH, reflux; (b) MeI, MeOH,
50 °C; (c) Tf2O, 2,6-lutidine, DCM, À78 °C; (d) N-Boc-piperazine, DIPEA, chloroben-
zene,
lw, 140 °C; (e) NaBH4, NiCl2, MeOH, THF, 0 °C, 1 h; (f) 4 N HCl in dioxane,
CH2Cl2; (g) RSO2Cl, Et3N, CH2Cl2, rt, 10 h.
Cl
O
O
a
b
NHNH2
+
Cl
Following the seven step synthetic sequence as shown below,
pyridinone analog 9 has been synthesized using 2,4-dihydroxy-
pyridine 29 as starting material (Scheme 4).
CO2H
N
N
N
N
18
19
20
21
c
In summary, we have identified a new series of GS inhibitors
with good in vitro antifungal activity. The effect of core structure
modifications on antifungal activity has been studied in detail. Fur-
ther optimization of the sulfonamide moiety led to the identifica-
tion of key aniline compounds with much improved systematic
exposure while retaining good antifungal activity. Further in vivo
study and SAR optimization of compound 11n to improve both
pharmacokinetic and biological activity will be discussed in the
near future.
O
O
EtO
S
O
d
S
O
Cl
N
N
N
N
O
N
N
N
N
22
6
Scheme 2. Reagents and conditions: (a) NaOAc, EtOH, reflux; (b) POCl3, PCl5;
(c) N-benzylsulfonylpiperazine, DIPEA, DMSO, MeOH,
THF,
D
; (d) EtOCH2CH2OH, NaH,
D
.
References and notes
NBoc
1. Maertens, J. A.; Boogaerts, M. A. Curr. Pharm. Des. 2000, 6, 225.
2. (a) Moudgal, V.; Sobel, J. Expert Opin. Pharmacother. 2010, 11, 2037; (b)
Kitamura, A. Expert Opin. Drug Disc. 2010, 5, 739; (c) Matejuk, A.; Leng, Q.;
Begum, M. D.; Woodle, M. C.; Scaria, P.; Chou, S.-T.; Mixson, A. J. Drugs Future
2010, 35, 197.
3. (a) Kondoh, O.; Inagaki, Y.; FuKuda, H.; Mizuguchi, E.; Ohya, Y.; Arisawa, M.;
Shimma, N.; Aoki, Y.; Sakatani, M.; Watanabe, T. Biol. Pharm. Bull. 2005, 28, 2138;
(b) Vargas, L. Y.; Castelli, M. V.; Kouznetsov, V. V.; Urbina, J. M.; Lopez, S. N.;
Sortino, M.; Enriz, R. D.; Ribas, J. C.; Zacchino, S. Bioorg. Med. Chem. Lett. 2003, 11,
1531.
b
c
N
a
O
N
N
N
HO
F
N
N
HO
OTf
f, g
HO
OH
NBoc
29
32
31
30
d
F
O
S
O
Br
NBoc
e
NBoc
N
O
N
O
N
O
N
N
N
N
4. Ting, P. C.; Aslanian, R. G.; Cao, J.; Kim, D. W.; Kuang, R.; Zhou, G.; Herr, R. J.;
Zych, A. J.; Yang, J.; Wu, H.; Zorn, N. World Patent 2008115381 September 25,
2008.
33
34
9
5. Ting, P. C.; Kuang, R.; Wu, H.; Aslanian, R. G.; Cao, J.; Kim, D. W.; Lee, J. F.;
Schwerdt, J.; Zhou, G.; Wainhaus, S.; Black, T. A.; Cacciapuoti, A.; McNicholas, P.
M.; Xu, Y.; Walker, S. S. Bioorg. Med. Chem. Lett. 2011, 21, 1819.
6. Glennon, R. A.; McKenney, J. D.; Lyon, R. A.; Titeler, M. J. Med. Chem. 1986, 29,
194.
Scheme 4. Reagents and conditions: (a) CF3SO3NPh, NaH, DMF, 5 h; (b) N-Boc-
piperazine, DMF, 80 °C, 6 h; (c) PhB(OH)2, Cu(OAc)2, Et3N, DCM, rt, 72 h; (d) NBS,
AcOH, rt, 3 h; (e) Bu3SnPhF, Pd(PPh3)4, LiCl, THF, reflux, 42 h; (f) 4 N HCl in dioxane,
CH2Cl2; (g) RSO2Cl, Et3N, CH2Cl2, rt, 10 h.
7. Sircar, I. J. Heterocycl. Chem. 1983, 20, 1473.
Boc-piperazine was used to displace the triflate to produce 27. Fur-
ther reduction of 27 gave intermediate 28. Removal of the Boc pro-
tecting group and sulfonylation produced the target compound 7.