S. Lee, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127543
BnO
BnO
BnO
OH
BnO
BnO
BnO
OH
O
O
O
O
O
O
O
OH
O
OH
2
3a
or
3b
MeO
MeO
a
b
24a
25a
2
BnO
BnO
BnO
BnO
BnO
BnO
O
O
OH
OH
O
O
HO
HO
O
O
O
O
MeO
MeO
24b
25b
Scheme 3. Synthesis of intermediates 25a and 25b. Reagents and conditions: (a) NaOMe, MeOH, 0 °C to rt, 16 h, 55 and 77%. (b) For 25a: Et
2
Zn, CH
2
I , toluene,
2
−
20 °C, 3 h, 76%. For 25b: Et
2
Zn, CH
2
I
2
, toluene, −78 °C to rt, 16 h (dr 6:1), 98%.
OH
OH
OTBS
OTBS
O
O
O
O
HO
*
O
*
*
TBSO
O
a
b
b
25a or b
*
a
O
*
O
7
O
O
O
MeO
MeO
MeO
MeO
39
2
6a or b
27a or b
OH
40a
d
OH
O
O
O
OBn
OR
EtO
*
RO
O
O
c
d
H
N
O
*
*
O
O
O
c
d
3
4
O
O
MeO
MeO
O
MeO
Cl
MeO
28a or b
29a or b R = Et
e
4
1a R = TBS
41b R = Bn
30a or b R = H
40b
OH
O
H
N
OH
O
F3C
H
N
O
O
e
O
Cl
MeO
O
O
3
1a
1b
f
Cl
MeO
2a
30a or b
4
OH
O
H
N
OH
41a or b
O
F3C
Cl
H
N
O
O
O
MeO
f
3
Cl
MeO
2b
4
Scheme 4. Synthesis of 31a and 31b. Reagents and conditions: (a) i) Tf
pyridine, DCM, −20 °C to rt; ii) DMF, pyridine, H O, 120 °C, 10 min, 81% and
3%. (b) DMP, DCM, rt, 0.5 h, 99%, and 83%. (c) triethyl phosphonoacetate,
NaH, benzene, rt, 1 h, 57% and 51% (d) CoCl , NaBH , MeOH/DMF, rt, 0.5 h,
2
O,
Scheme 6. Synthesis of 42a and 42b. Reagents and conditions: (a) TBSCl,
2
imidazole, DMF, rt, 6 h, 66%. (b) OsO
4
, NMO, NaIO
4
, THF/H
2
O, rt, 1.5 h, 70%.
9
+
-
(
c) DMP, DCM, rt, 3 h, 80–88%. (d) LDA, 4-ClPhNH(C]O)CH
2
P
Ph
3
Cl (see
2
4
Supporting Information compound S2), THF/toluene, 0 °C to rt, 3 h, 73% and
6
2% and 87% (e) LiOH, THF/H O, rt, 3 h, 86% and 85%. (f) 4-chloro-3-(tri-
2
5
1
1% (e) TBAF, THF, 0 °C to rt, 0.5 h, 22% (f) 10% Pd/C, H
2
(1 atm), MeOH, rt,
fluoromethyl)aniline, EDC•HCl, HOAt, DMF, rt, 16 h, 81% and 71%.
h, 46%.
CpIMPDH and HsIMPDH2 using Dynafit.40
HsIMPDH2 (Ki,app = 0.35 µM), in contrast to all prior reported
CpIMPDH inhibitors. Since electron withdrawing groups were preferred
in previously developed CpIMPDH inhibitors, the methoxy group in 8
was replaced with a chloro (9). This compound showed similar in-
hibitory potency as 8 for both enzymes. However, replacing with a
trifluoromethyl (10) increased potency against both enzymes. Trans-
posing the para-chloro to the ortho-position (11) resulted in loss of
CpIMPDH inhibitory activity. This was consistent with the SAR of other
CpIMPDH inhibitors, possibly resulting from a clash with Y358′ and loss
Introducing an anilide as the common fragment to MPA improved
CpIMPDH inhibition. For example, 8, which incorporated the anilide
from 4 with MPA, potently inhibited CpIMPDH with Ki,app value of
0
.046 µM (Table 1). Interestingly, the compound also inhibited
OH
OH
OBn
O
O
O
HO
HO
a
R
c
O
O
O
O
MeO
MeO
MeO
9
of a halogen bond with G357′. A survey of various electron with-
7
32 R = CHO
3 R = CH2OH
34
b
drawing groups at the 4-position demonstrated that chloro (12) pro-
vided potent and balanced CpIMPDH and HsIMPDH2 inhibition.
3
Cl
O
OBn
O
OR
O
O
O
O
d
RO
f
N
H
O
O
OH
OH
O
O
H
MeO
MeO
N
a
HO2C
MeO
b
32
O
O
O
3
3
5 R = Et
6 R = H
37 R = Bn
38 R = H
e
g
Cl
MeO
Scheme 5. Synthesis of 38. Reagents and conditions: (a) OsO
THF/H O, rt, 1.5 h. (b) NaBH , EtOH, rt, 3 h, 70–81%. (c) benzyl bromide,
TBAF, rt, 6.5 h, 81–89%. (d) InCl , ethyl diazoacetate, DCM, rt, 16 h, 57%. (e)
LiOH, MeOH/H O, rt, 3 h, 76–95%. (f) EDC•HCl, HOAt, 4-chloroaniline, DMF,
rt, 16 h, 65–80%. (g) 10% Pd/C, H (1 atm), MeOH, rt, 1 h, 27–56%.
4
, NMO, NaIO
4
,
43
44
2
4
Scheme 7. Synthesis of 44. Reagents and conditions: (a) NaClO
methyl-2-butene, t-BuOH/H O, rt, 4 h (b) EDC, DIPEA, 4-chloroaniline, THF/
DMF, rt, 16 h, 38% over two steps.
2
, NaH
2
PO , 2-
4
3
2
2
2
3