Journal of Medicinal Chemistry
Article
1
amine (23). H NMR (400 MHz, CDCl ): δ 8.12 (s, 1H), 8.03 (d, J
=
(t, J = 8.8 Hz, 1H), 3.20 (t, J = 8.8 Hz, 2H), 2.85 (s, 3H), 2.60 (s,
3
1
3
13
8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.49 (s, 1H), 6.95−6.83 (m,
H), 6.72 (dd, J = 8.7, 4.0 Hz, 1H), 5.68 (s, 1H), 4.88 (d, J = 4.9 Hz,
H), 4.66 (t, J = 8.7 Hz, 2H), 3.45 (t, J = 8.7 Hz, 2H), 3.16 (s, 3H),
3H), 2.36 (s, 3H). C NMR (101 MHz, DMSO-d ): δ C NMR
6
1
2
3
(101 MHz, DMSO-d ): δ 156.9, 156.1, 154.5, 154.2, 152.2, 147.2,
6
143.9, 142.1, 133.3, 130.1, 129.8, 127.3, 124.7, 121.8, 121.6, 114.5,
+
.14 (s, 3H). LC−MS: [M + H] , 517.09.
114.2, 108.8, 108.3, 72.0, 43.8, 37.9, 29.0, 19.4, 18.7. LC−MS: [M +
+
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-fluoro-
H] , 468.14.
phenyl)-1(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-amine (24).
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methyl-6-
1
H NMR (400 MHz, MeOH-d ): δ 8.68 (s, 1H), 7.52−7.31 (m,
(trifluoromethyl)pyridin-3-yl)-1-(methylsulfonyl)imidazo[1,5-c]-
4
1
pyrimidin-5-amine (33). H NMR (400 MHz, MeOH-d ): δ 8.93 (s,
3
H), 7.18−7.04 (m, 2H), 6.92−6.81 (m, 1H), 6.66 (dd, J = 8.6, 3.8
4
1
H), 8.79 (t, J = 5.0 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 7.9
Hz, 1H), 4.84 (d, J = 1.0 Hz, 2H), 4.59 (t, J = 8.7 Hz, 2H), 3.39 (t, J =
+
Hz, 1H), 7.46 (s, 1H), 6.97 (dd, J = 10.3, 8.6 Hz, 1H), 6.73 (dd, J =
8
.7 Hz, 2H), 3.00 (s, 3H). LC−MS: [M + H] , 457.10.
8
3
.6, 3.9 Hz, 1H), 4.84−4.66 (m, 2H), 4.57 (t, J = 8.7 Hz, 2H), 3.40−
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methyl-4-
+
.29 (m, 2H), 3.02 (s, 3H), 2.35 (s, 3H). LC−MS: [M + H] , 522.11.
(
methylsulfonyl)phenyl)-1-(methylsulfonyl)imidazo[1,5-c]-
1
pyrimidin-5-amine (25). H NMR (400 MHz, DMSO-d ): δ 8.92 (s,
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-
6
1
H-pyrazol-4-yl)-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-
1
1
1
H), 8.73 (s, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.73 (dd, J = 7.9, 2.0 Hz,
H), 7.45 (d, J = 7.9 Hz, 1H), 7.36 (s, 1H), 6.96 (dd, J = 10.3, 8.6 Hz,
H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 4.75 (q, J = 14.4 Hz, 2H), 4.56 (t,
1
amine (34). H NMR (400 MHz, MeOH-d ): δ 8.63 (s, 1H), 7.76 (s,
4
1
8
H), 7.59 (s, 1H), 7.44 (s, 1H), 6.85 (t, J = 9.6 Hz, 1H), 6.64 (dd, J =
.4, 3.6 Hz, 1H), 4.81 (s, 2H), 4.57 (t, J = 8.4 Hz, 2H), 3.94 (s, 3H),
J = 8.7 Hz, 2H), 3.41−3.29 (m, 2H), 3.23 (s, 3H), 2.99 (s, 3H), 2.20
+
3.36 (t, J = 8.8 Hz, 2H), 3.00 (s, 3H), 2.66 (s, 2H). LC−MS: [M +
(
s, 3H). LC−MS: [M + H] , 531.10.
+
H] , 443.12.
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methyl-
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(tetrahydro-
2H-pyran-4-yl)imidazo[1,5-c]pyrimidin-5-amine (59). 3,6-Dihydro-
pyridin-3-yl)-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-amine
1
(
26). H NMR (400 MHz, MeOH-d ): δ 8.78 (d, J = 1.5 Hz, 1H),
4
2
H-pyran-4-boronic acid pinacol ester (290 mg, 1.38 mmol),
8
.73 (dd, J = 5.9, 1.8 Hz, 1H), 8.44 (dt, J = 7.9, 1.5 Hz, 1H), 7.95 (dd,
J = 7.8, 6.0 Hz, 1H), 7.59 (d, J = 0.9 Hz, 1H), 6.88 (td, J = 9.5, 9.1,
.9 Hz, 1H), 6.67 (dd, J = 8.6, 4.0 Hz, 1H), 4.88 (d, J = 4.9 Hz, 2H),
Pd(PPh3) (80 mg, 0.069 mmol), and Na CO (285 mg) were
4
2
3
added to a solution (dioxane/H O = 10:2.5 mL) of compound 56
1
4
3
2
(
250 mg, 0.69 mmol). The resulting mixture was stirred under N at
.60 (td, J = 8.7, 1.5 Hz, 2H), 3.43 (t, J = 8.7 Hz, 2H), 3.11−3.00 (m,
2
+
90 °C overnight. The mixture was then cooled to rt, and the solvent
was removed in vacuo and purified by column chromatography
H), 2.63 (s, 3H). LC−MS: [M + H] , 454.12.
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methyl-
(
eluting with 0−5% MeOH/DCM) to obtain the title compound 59
pyridin-3-yl)-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-amine
1
+
(
27). H NMR (400 MHz, MeOH-d ): δ 8.87−8.80 (m, 1H), 8.76 (d,
as a white solid in 80% yield. LC−MS: [M + H] , 367.14.
4
J = 0.9 Hz, 1H), 8.51 (dd, J = 8.3, 2.1 Hz, 1H), 7.95 (d, J = 8.3 Hz,
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(tetrahydro-
H-pyran-4-yl)imidazo[1,5-c]pyrimidin-5-amine (60). Pd/C (100
2
1
3
8
H), 7.62 (d, J = 0.8 Hz, 1H), 6.91−6.82 (m, 1H), 6.66 (dt, J = 9.0,
.4 Hz, 1H), 4.85 (s, 2H), 4.60 (td, J = 8.7, 1.4 Hz, 2H), 3.41 (t, J =
mg, 10% wt) was added to a solution of compound 59 (1 g, 2.70
mmol) in MeOH (25 mL). The reaction mixture was degassed with
+
.7 Hz, 2H), 3.18 (s, 3H), 2.86 (s, 3H). LC−MS: [M + H] , 454.12.
H and stirred under an H atmosphere for 6 h at rt. The mixture was
8
-(6-Cyclopropylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofur-
2
2
an-4-yl)methyl)-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-
then filtered through Celite and washed with MeOH. Concentration
under reduced pressure yielded the desired product. LC−MS: [M +
1
amine (28). H NMR (400 MHz, DMSO-d ): δ 8.92 (s, 1H), 8.86 (s,
6
+
1
=
H), 8.58 (s, 1H), 8.01 (s, 1H), 7.48 (d, J = 11.0 Hz, 2H), 6.96 (dd, J
10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 4.75 (d, J = 4.6
Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 3.32 (t, J = 8.7 Hz, 2H), 3.11 (s,
H] , 369.17.
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-iodo-8-(tet-
rahydro-2H-pyran-4-yl)imidazo[1,5-c]pyrimidin-5-amine (61). NIS
(
(
82 mg, 0.4 mmol) was added at 0 °C to a solution of compound 60
3
3
1
1
H), 2.26 (dd, J = 9.1, 4.6 Hz, 1H), 1.25−1.11 (m, 2H), 1.07 (t, J =
.6 Hz, 2H). 13C NMR (100 MHz, DMSO-d ): δ 159.7, 156.9, 156.2,
160 mg, 0.43 mmol) in DMF (4 mL) and stirred at rt for 15 min.
6
The mixture was extracted with DCM (4 × 50 mL), washed with
54.5, 143.5, 141.9, 130.4, 130.3, 129.7, 126.8, 121.9, 121.8, 121.3,
14.5, 114.3, 108.9, 108.8, 72.0, 43.9, 37.9, 37.8, 29.0, 15.6, 11.5. LC−
MS: [M + H] , 480.14.
brine (30 mL), dried (Na SO ), and filtered. The filtrate was
2
4
+
concentrated, and the residue was purified by column chromatog-
raphy (eluting with 20−50% EtOAc/hexane) to afford the title
compound 61 in 60% yield (127 mg, 0.25 mmol, 70%). LC−MS: [M
8
-(6-(Difluoromethyl)pyridin-3-yl)-N-((5-fluoro-2,3-dihydroben-
zofuran-4-yl)methyl)-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-
1
+
amine (29). H NMR (400 MHz, MeOH-d ): δ 8.74 (s, 1H), 8.73−
+ H] , 495.04.
4
8
(
.67 (m, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.54
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(methylsul-
fonyl)-8-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-c]pyrimidin-5-
amine (35). A mixture of compound 61 (50 mg, 0.1 mmol),
s, 1H), 6.96−6.77 (m, 2H), 6.73−6.61 (m, 1H), 4.86 (d, J = 1.1 Hz,
H), 4.60 (t, J = 8.7 Hz, 2H), 3.41 (t, J = 8.7 Hz, 2H), 3.11 (s, 3H).
2
+
MeSO Na (30 mg. 0.3 mmol), and CuI (57 mg. 0.3 mmol) in DMSO
LC−MS: [M + H] , 490.10.
2
(
2 mL) was bubbled with N for 5 min and the sealed tube was then
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(methylsul-
2
heated in a microwave reactor at 120 °C for 20 min and then at 100
fonyl)-8-(6-(trifluoromethyl)pyridin-3-yl)imidazo[1,5-c]pyrimidin-5-
1
amine (30). H NMR (400 MHz, CDCl ): δ 8.74 (d, J = 2.1 Hz, 1H),
°C for 3 h. The mixture was concentrated, and the residue was
3
8
(
.39 (s, 1H), 8.05−7.91 (m, 1H), 7.78 (dd, J = 8.1, 0.7 Hz, 1H), 7.49
purified by HPLC to afford the title compound 35 (21 mg, 0.05
1
s, 1H), 6.89−6.72 (m, 1H), 6.65 (dd, J = 8.7, 3.9 Hz, 1H), 6.46 (s,
mmol) in 50% yield. H NMR (400 MHz, DMSO-d
6
): δ 8.80 (s, 1H),
1
3
H), 4.85 (s, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.41 (t, J = 8.7 Hz, 2H),
8.44 (t, J = 5.1 Hz, 1H), 7.49 (s, 1H), 6.94 (dd, J = 10.3, 8.7 Hz, 1H),
6.70 (dd, J = 8.7, 3.9 Hz, 1H), 4.68 (d, J = 4.4 Hz, 2H), 4.54 (t, J =
8.7 Hz, 2H), 3.95 (dd, J = 11.1, 3.8 Hz, 2H), 3.66 (ddd, J = 11.7, 8.4,
3.3 Hz, 1H), 3.40 (d, J = 1.9 Hz, 1H), 3.36 (s, 3H), 3.29 (t, J = 8.7
Hz, 2H), 1.81 (d, J = 13.6 Hz, 2H), 1.67 (qd, J = 12.3, 4.2 Hz, 2H).
+
.08 (s, 3H). LC−MS: [M + H] , 508.09.
N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(methylsul-
fonyl)-8-(6-(methylsulfonyl)pyridin-3-yl)imidazo[1,5-c]pyrimidin-5-
1
amine (31). H NMR (400 MHz, MeOH-d ): δ 8.79 (dd, J = 2.0, 1.0
4
+
Hz, 1H), 8.75 (s, 1H), 8.23−8.01 (m, 2H), 7.57 (s, 1H), 6.93−6.80
m, 1H), 6.67 (dd, J = 8.6, 3.9 Hz, 1H), 4.84 (d, J = 1.0 Hz, 2H), 4.60
t, J = 8.7 Hz, 2H), 3.41 (t, J = 8.8 Hz, 2H), 3.28 (s, 3H), 3.14 (s,
LC−MS: [M + H] , 447.14.
(
(
3
4-(5-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-
(methylsulfonyl)imidazo[1,5-c]pyrimidin-8-yl)tetrahydro-2H-thio-
1
+
pyran 1,1-Dioxide (36). H NMR (400 MHz, DMSO-d ): δ 8.83 (s,
H). LC−MS: [M + H] , 518.08.
6
1H), 8.51 (t, J = 5.1 Hz, 1H), 7.54 (d, J = 0.7 Hz, 1H), 6.93 (dd, J =
8
-(2,6-Dimethylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofur-
an-4-yl)methyl)-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-
10.3, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 4.67 (d, J = 4.3 Hz,
2H), 4.55 (t, J = 8.7 Hz, 2H), 3.72−3.59 (m, 1H), 3.38 (s, 3H), 3.31
(t, J = 8.7 Hz, 2H), 3.27−3.06 (m, 4H), 2.31−2.19 (m, 2H), 2.19−
1
amine (32). H NMR (400 MHz, MeOH-d ): δ 8.54 (s, 1H), 8.05 (d,
4
J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 6.65 (t, J = 9.2
Hz, 1H), 6.44 (dd, J = 8.6, 3.6 Hz, 1H), 4.63 (t, J = 6.4 Hz, 2H), 4.37
+
2.04 (m, 2H). LC−MS: [M + H] , 495.10.
L
J. Med. Chem. XXXX, XXX, XXX−XXX