Journal of Medicinal Chemistry
Article
(d, J = 1.52 Hz, 1 H), 7.65 (d, J = 2.02 Hz, 1 H), 7.59 (dd, J = 8.59, 2.02
Hz, 1 H), 6.60 (dd, J = 2.53, 1.52 Hz, 1 H), 4.36 (tt, J = 12.38, 3.28 Hz, 1
H), 4.04 (s, 3 H), 2.99 (s, 3 H), 1.61 (dd, J = 12.13, 3.03 Hz, 2 H), 1.42
(t, J = 12.38 Hz, 2 H), 1.29 (br s, 1 H), 1.22 (s, 6 H), 1.09 (s, 6 H).
2-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-
1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-1-yl)phenol (10). Boron tri-
bromide (1.0 M solution in heptane, 0.35 mL, 0.35 mmol) was added to
a solution of 9 (30 mg, 0.070 mmol) in DCM (1.5 mL) under nitrogen.
After this was stirred for 2 h, methanol (5 mL) was added, and the
resulting solution was subjected to General Procedure B. The
concentrated filtrate was sonicated in MeOH (2 mL) resulting in the
formation of a precipitate, which was isolated by filtration to provide the
title compound as a pale yellow solid (15 mg, 51% yield). MS (ESI) m/z
413.3 [M + 1]. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 2.02 Hz,
1 H), 7.99 (d, J = 8.59 Hz, 1 H), 7.73−7.78 (m, 1 H), 7.47 (d, J = 1.52
Hz, 1 H), 7.36 (d, J = 8.59 Hz, 1 H), 6.53−6.58 (m, 1 H), 4.33 (t, J =
12.13 Hz, 1 H), 2.99 (s, 3 H), 1.58−1.69 (m, 2 H), 1.47 (t, J = 12.13 Hz,
2 H), 1.23 (s, 6 H), 1.12 (s, 6 H).
2-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-
1,3,4-thiadiazol-2-yl)-4-(1H-pyrazol-1-yl)phenol (11). From 38d
(100 mg, 0.23 mmol), as described in General Procedure C, the title
compound was obtained as a brown solid (47 mg, 46% yield). MS (ESI)
m/z 413.4 [M + 1]. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.02
Hz, 1 H), 8.33 (d, J = 3.03 Hz, 1 H), 7.64−7.72 (m, 2 H), 7.04 (d, J =
8.59 Hz, 1 H), 6.50 (t, J = 2.02 Hz, 1 H), 4.29−4.38 (m, 1 H), 3.00 (s, 3
H), 1.64 (dd, J = 11.62, 3.03 Hz, 2 H), 1.45 (t, J = 12.13 Hz, 2 H), 1.22
(s, 6 H), 1.10 (s, 6 H).
5-(2-Methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-
(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine
(12). From 41a (100 mg, 0.20 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.26 mmol) as described in
General Procedure A, the title compound was obtained as a clear glassy
solid (25 mg, 31% yield) after purification by preparative HPLC (5 mM
NH4OH modifier). MS (ESI) m/z 427.4 [M + 1]. 1H NMR (400 MHz,
DMSO-d6) δ 13.03 (br s, 1 H), 8.32 (br s, 1 H), 8.05 (d, J = 8.08 Hz, 2
H), 7.41 (d, J = 1.52 Hz, 1 H), 7.34 (dd, J = 8.08, 1.52 Hz, 1 H), 4.35 (tt,
J = 12.44, 2.97 Hz, 1 H), 4.00 (s, 3 H), 2.98 (s, 3 H), 1.61 (dd, J = 11.87,
3.28 Hz, 2 H), 1.36−1.47 (m, 2 H), 1.27 (br s, 1 H), 1.21 (s, 6 H), 1.09
(s, 6 H).
mg, 0.19 mmol), as described in General Procedure A, after preparative
HPLC (5 mM NH4OH modifier) the title compound was obtained as a
1
yellow solid (30 mg, 44% yield). MS (ESI) m/z 468.4 [M + 1]. H
NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.08 Hz, 1 H), 7.80 (d, J =
7.07 Hz, 1 H), 7.48 (d, J = 1.52 Hz, 1 H), 7.44 (dd, J = 8.08, 1.52 Hz, 1
H), 6.83 (d, J = 2.02 Hz, 1 H), 6.67 (dd, J = 7.07, 2.02 Hz, 1 H), 4.34−
4.44 (m, 1 H), 4.05 (s, 3 H), 3.47 (s, 3 H), 2.99 (s, 3 H), 1.61 (dd, J =
12.13, 3.03 Hz, 2 H), 1.42 (t, J = 12.13 Hz, 2 H), 1.28 (br s, 1 H), 1.22
(s, 6 H), 1.09 (s, 6 H).
4-(3-Hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-
yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)-1-methylpyridin-
2(1H)-one (17). From 16 (25 mg, 0.053 mmol), as described in
General Procedure C, the title compound was obtained as a dark yellow
glassy solid (14 mg, 57% yield). Purification was effected by a
dissolution of the crude product in EtOAc followed by a sonication and
isolation of the resulting solids by filtration. MS (ESI) m/z 454.4 [M +
1]. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 8.08 Hz, 1 H), 7.78
(d, J = 7.07 Hz, 1 H), 7.23−7.28 (m, 2 H), 6.62 (d, J = 2.02 Hz, 1 H),
6.52 (dd, J = 7.07, 2.02 Hz, 1 H), 4.31−4.38 (m, 1 H), 3.45 (s, 3 H),
3.00 (s, 3 H), 1.64 (d, J = 12.13 Hz, 2 H), 1.46 (t, J = 9.60 Hz, 2 H), 1.23
(s, 6 H), 1.11 (s, 6 H).
N-Methyl-5-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-N-
(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine
hydrochloride (18). Step 1. 5-(5-Bromopyridin-2-yl)-N-methyl-N-
(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (49 mg,
30% yield) was prepared from 44e (129 mg, 1.29 mmol) in a manner
analogous to the method described above for the preparation of 45a.
Purification by preparative HPLC (5 mM NH4OH modifier). MS
(ESI) m/z 412.2 [M+2]. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J =
3.03 Hz, 1 H), 8.20−8.16 (m, 1 H), 8.00 (d, J = 8.59 Hz, 1 H), 4.32−
4.21 (m, 1 H), 3.02 (s, 3 H), 1.62 (dd, J = 12.13, 3.54 Hz, 2 H), 1.43 (t, J
= 12.13 Hz, 2 H), 1.20 (s, 6 H), 1.08 (s, 6 H).
Step 2: To a stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25 mg, 0.121 mmol) and 5-(5-
bromopyridin-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-
1,3,4-thiadiazol-2-amine (45 mg, 0.11 mmol) in dioxane (1 mL) was
added Pd(PPh3)4 (6 mg, 0.005 mmol) followed by a solution of
Na2CO3 (35 mg, 0.33 mmol) in water (0.25 mL). The reaction mixture
was purged with nitrogen, sealed, and heated at 120 °C for 30 min
under microwave irradiation. After a standard aqueous workup and
metal scavenging by General Procedure D, a white solid was obtained.
The solid was suspended in dioxane (1 mL), and 4 M HCl in dioxane (1
mL) was added. The yellow slurry was stirred at room temperature for
72 h. Isolation of the solids by filtration provided the title compound
(24 mg, 49% yield) as the monohydrochloride salt (as determined by
2-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-
1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-4-yl)phenol (13). From 12
(48 mg, 0.11 mmol), as described in General Procedure C, the title
compound was obtained (10 mg, 21% yield). MS (ESI) m/z 413.1 [M +
1
1]. H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.31−7.88 (m,
2H), 7.80 (d, J = 8.6 Hz, 1H), 7.23−7.13 (m, 2H), 4.30 (tt, J = 12.9, 3.6
Hz, 1H), 2.99 (s, 3H), 1.62 (dd, J = 12.1, 3.4 Hz, 2H), 1.43 (t, J = 12.2
Hz, 2H), 1.21 (s, 6H), 1.09 (s, 6H).
1
counterion analysis). MS (ESI) m/z 412.3 [M+1]. H NMR (400
MHz, DMSO-d6) δ 9.03 (d, J = 11.12 Hz, 1 H), 8.85 (d, J = 2.02 Hz, 1
H), 8.33 (s, 1 H), 8.13−8.07 (m, 1 H), 8.07−7.93 (m, 3 H), 4.55−4.44
(m, 1 H), 3.90 (s, 3 H), 3.07 (s, 3 H), 2.02−1.87 (m, 4 H), 1.50 (s, 6 H),
1.45 (s, 6 H).
5-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-meth-
yl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-
amine (14). From 41a (50 mg, 0.098 mmol) and 1-methyl-4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (27 mg, 0.13 mmol)
as described in General Procedure A, the title compound was obtained
as a white solid (14 mg, 33% yield) after purification by preparative
HPLC (5 mM NH4OH modifier). MS (ESI) m/z 441.4 [M + 1]. 1H
NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1 H), 8.05 (d, J = 8.08 Hz, 1 H),
7.98 (s, 1 H), 7.37 (d, J = 1.52 Hz, 1 H), 7.29 (dd, J = 8.59, 1.52 Hz, 1
H), 4.31−4.40 (m, 1 H), 3.99 (s, 3 H), 3.88 (s, 3 H), 2.98 (s, 3 H), 1.61
(dd, J = 11.62, 2.53 Hz, 2 H), 1.42 (t, J = 12.13 Hz, 2 H), 1.27 (br s, 1
H), 1.22 (s, 6 H), 1.09 (s, 6 H).
2-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-
1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol
(15). From 14 (138 mg, 0.31 mmol), as described in General Procedure
C, the title compound was obtained as a brown solid (19 mg, 14%
yield). MS (ESI) m/z 427.4 [M + 1]. 1H NMR (400 MHz, DMSO-d6)
δ 8.14 (s, 1 H), 7.79−7.86 (m, 2 H), 7.11−7.16 (m, 2 H), 4.25−4.34
(m, 1 H), 3.87 (s, 3 H), 2.99 (s, 3 H), 1.62 (dd, J = 12.13, 3.03 Hz, 2 H),
1.43 (t, J = 12.13 Hz, 2 H), 1.21 (s, 6 H), 1.09 (s, 6 H).
N - M e t h y l - 5 - ( 4 - ( 1 - m e t h y l - 1 H - p y r a z o l - 4 - y l ) - 2 -
(trifluoromethyl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-
yl)-1,3,4-thiadiazol-2-amine (19). From 41c (49 mg, 0.089 mmol)
and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyr-
azole (24 mg, 0.12 mmol) as described in General Procedure A, the title
compound was obtained as a glassy solid (25 mg, 57% yield). The crude
product was purified by preparative HPLC (5 mM NH4OH modifier).
MS (ESI) m/z 479.4 [M + 1]. 1H NMR (400 MHz, DMSO-d6) δ 8.42
(s, 1 H), 8.08 (s, 1 H), 8.03−8.06 (m, 1 H), 7.95 (dd, J = 8.08, 1.52 Hz,
1 H), 7.69 (d, J = 8.08 Hz, 1 H), 4.23−4.32 (m, 1 H), 3.89 (s, 3 H), 3.00
(s, 3 H), 1.63 (dd, J = 12.13, 3.54 Hz, 2 H), 1.43 (t, J = 12.13 Hz, 2 H),
1.29 (br s, 1 H), 1.20 (s, 6 H), 1.09 (s, 6 H).
1-Methyl-4-(3-methyl-4-(5-(methyl(2,2,6,6-tetramethylpi-
peridin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)pyridin-
2(1H)-one (20). From 41b (77 mg, 0.12 mmol) and 1-methyl-4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (37
mg, 0.16 mmol) as described in General Procedure A, the title
compound was afforded as a clear glassy solid (20 mg, 36% yield). The
crude product was purified by preparative HPLC (5 mM NH4OH
modifier). MS (ESI) m/z 452.4 [M + 1]. 1H NMR (400 MHz, DMSO-
d6) δ 7.80 (d, J = 7.07 Hz, 1 H), 7.75 (s, 1 H), 7.66 (s, 2 H), 6.75 (d, J =
4-(3-Methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-
yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)-1-methylpyridin-
2(1H)-one (16). From 41a (75 mg, 0.15 mmol) and 1-methyl-4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (45
4757
J. Med. Chem. 2021, 64, 4744−4761