Journal of Medicinal Chemistry
Article
mg, 30%). 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.05 (d, J = 7.8
Hz, 2H). 7.54−7.48 (m, 2 H), 7.45−7.41 (m, 1 H), 7.03 (s, 1 H),
5.77 (s, 1 H), 2.53 (s, 3 H), 1.65−1.52 (m, 4 H), 1.20 (s, 9 H), 1.12
(br s, 6H). MS (C26H34N4O3): m/z 451 (M + H)+.
(2S)-2-(2-([1,1′-Biphenyl]-3-yl)-7-(8-fluoro-5-methylchro-
man-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-
butoxy)acetic Acid ((S,S)-24). The title compound was prepared
from (2S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(8-fluoro-
5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-
2-tert-Butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-
methyl-2-p-tolylpyrazolo[1,5-a]pyrimidin-6-yl)acetic Acid,
TFA Salt (S,S and R,R)-20. A mixture of the TFA salt of 47 (8
mg, 0.016 mmol), Pd(PPh3)4 (2.69 mg, 2.326 μmol), 2-(8-fluoro-5-
methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.06
mg, 0.031 mmol), 2 M K3PO4 solution (50 μL), and DMF (0.7
mL) was heated in a microwave reactor at 130 °C for 15 min. The
reaction mixture was filtered and the filtrate purified by preparative
HPLC to afford methyl 2-tert-butoxy-2-(7-(8-fluoro-5-methylchro-
man-6-yl)-5-methyl-2-p-tolylpyrazolo[1,5-a]pyrimidin-6-yl)acetate as
1
acetate in a manner similar to that described for (S,S)-27. H NMR
(500 MHz, CDCl3) δ (ppm): 8.05−7.98 (m, 1H), 7.81 (d, J = 7.6 Hz,
1H), 7.65−7.58 (m, 2H), 7.55 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.5 Hz,
3H), 7.40−7.33 (m, 1H), 6.98−6.90 (m, 2H), 5.09 (s, 1H), 4.38−
4.27 (m, 2H), 2.82−2.66 (m, 5H), 2.15 (d, J = 6.1 Hz, 2H), 1.93 (s,
3H), 1.21 (s, 9H). MS (C35H34FN3O4): m/z 580 (M + H)+.
2-(2-([1,1′-Biphenyl]-3-yl)-7-(4,4-dimethylpiperidin-1-yl)-5-
methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic
Acid ((S and R)-25). A mixture of 46 (90 mg, 0.230 mmol),
Pd(PPh3)4 (40 mg, 0.035 mmol), [1,1′-biphenyl]-3-ylboronic acid
(45.6 mg, 0.230 mmol), 2 M K2CO3 solution (300 μL), and DMF (4
mL) was heated in a microwave reactor at 70 °C for 60 min. The
mixture was filtered and the filtrate purified by preparative HPLC to
afford methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-chloro-5-methylpyrazolo-
[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as the TFA salt (47 mg,
35.3%). MS (C26H26ClN3O3): m/z 464 (M + H)+. A mixture of
methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-chloro-5-methylpyrazolo[1,5-a]-
pyrimidin-6-yl)-2-(tert-butoxy)acetate, TFA salt (25 mg, 0.043
mmol), 4,4-dimethylpiperidine HCl salt (16.13 mg, 0.108 mmol),
and DIEA (0.038 mL, 0.216 mmol) in CH2Cl2 (3 mL) was stirred at
rt for 18 h. The solvent was evaporated, dioxane (1 mL) and NaOH
(1 mL, 1.0 mmol) added and the mixture heated at 50 °C for 1 h. The
mixture was filtered and the filtrate was purified by preparative HPLC
to afford (S and R)-25 as the TFA salt (1.5 mg, 6.7%). 1H NMR (500
MHz, DMSO-d6) δ (ppm): 8.36 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H),
7.79−7.71 (m, 3H), 7.61 (t, J = 7.63 Hz, 1H), 7.52 (t, J = 7.27 Hz,
2H), 7.44−7.41 (m, 1H), 7.11 (s, 1H), 5.63 (br s, 1H), 3.48−3.26
(m, 4H), 2.54 (s, 3H), 1.67−1.51 (m, 4H), 1.18 (s, 9H), 1.12 (br s,
6H). MS (C32H38N4O3): m/z 527 (M + H)+.
2-(2-(3-(Benzyloxy)phenyl)-7-(4,4-dimethylpiperidin-1-yl)-
5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic
Acid ((S and R)-26). The title compound was prepared from methyl
2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-tert-
butoxyacetate in a manner similar to that described for (S and R)-25.
1H NMR (500 MHz, DMSO-d6) δ (ppm): 7.72−7.67 (m, 1H), 7.63
(d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.44−7.41 (m, 3H),
7.37−7.34 (m, 1H), 7.07 (dd, J = 8.2, 1.8 Hz, 1H), 7.03 (s, 1H), 5.71
(s, 1H), 5.21 (s, 2H), 3.36 (br s, 4H), 2.52 (s, 3H), 1.51−1.67 (m,
4H), 1.19 (s, 9H), 1.11 (br s, 6H). MS (C33H40N4O4): m/z 557 (M +
H)+.
(2S)-2-(tert-Butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-
5-methyl-2-(2′-methyl-[1,1′-biphenyl]-3-yl)pyrazolo[1,5-a]-
pyrimidin-6-yl)acetic Acid ((S,S)-27). A mixture of dicyclohexyl-
(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (595 mg, 1.449
mmol), Pd(OAc)2 (163 mg, 0.725 mmol), o-tolylboronic acid (296
mg, 2.174 mmol), 2 M K3PO4 solution (200 μL), and 55 (400 mg,
0.725 mmol) in DMF (1.5 mL) was heated in a microwave reactor at
130 °C for 30 min. The mixture was filtered and the filtrate purified
by silica gel chromatography to afford (2S)-methyl 2-(tert-butoxy)-2-
(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(2′-methyl-[1,1′-bi-
phenyl]-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (225.6 mg,
51.2%). 1H NMR (500 MHz, CDCl3) δ (ppm): 7.86−7.76 (m,
2H), 7.42 (t, J = 7.8 Hz, 1H), 7.29−7.26 (m, 5H), 6.88−6.86 (m,
2H), 4.99 (s, 1H), 4.39−4.27 (m, 2H), 3.64 (s, 3H), 2.83−2.70 (m,
5H), 2.26 (s, 3H), 2.22−2.13 (m, 2H), 1.84 (s, 3H), 1.16 (s, 9H). MS
(C37H38FN3O4): m/z 608 (M + H)+. 1 N NaOH aqueous solution (9
mL, 9 mmol) was added to a solution of (2S)-methyl 2-(tert-butoxy)-
2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(2′-methyl-[1,1′-
biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (1.28 g, 2.1
mmol) in dioxane (12 mL) and the mixture stirred at 50 °C for 2
h. The mixture was diluted with H2O (50 mL), neutralized with
AcOH, and extracted with EtOAc (3 × 100 mL). The organic phase
was combined, dried over Na2SO4, concentrated and the crude
product purified by preparative HPLC to afford (S,S)-27 (840 mg,
66%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.86−7.75 (m, 2H),
7.50 (t, J = 7.7 Hz, 1H), 7.40−7.22 (m, 5H), 7.18 (s, 1H), 7.09 (d, J =
1
the TFA salt (5 mg, 49.9%). H NMR (400 MHz, CDCl3) δ (ppm):
7.72 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.01 (s, 1 H), 6.89
(d, J = 10.5 Hz, 1H), 5.06 (s, 1 H), 4.40−4.33 (m, 2 H), 3.68 (s, 3
H), 2.86 (s, 3 H), 2.81−2.76 (m, 2 H), 2.38 (s, 3 H), 2.23−2.16 (m, 2
H), 1.86 (s, 3 H), 1.19 (s, 9 H). MS (C31H34FN3O4): m/z 532 (M +
H)+. A mixture of 1 N LiOH aqueous solution (0.5 mL, 0.5 mmol)
and methyl 2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-
methyl-2-p-tolylpyrazolo[1,5-a]pyrimidin-6-yl)acetate, TFA salt (5
mg, 7.74 μmol) in dioxane (0.5 mL) was stirred at 50 °C for 1 h.
The mixture was filtered and the filtrate purified by preparative HPLC
1
to afford (S,S and R,R)-20 (4 mg, 82%) as the TFA salt. H NMR
(500 MHz, MeOD) δ (ppm): 7.71 (d, J = 8.2 Hz, 2H), 7.21 (d, J =
7.9 Hz, 2H), 6.94 (d, J = 10.7 Hz, 1H), 6.88 (s, 1 H), 5.01 (s, 1 H),
4.40−4.24 (m, 2 H), 2.86−2.78 (m, 2 H), 2.76 (s, 3 H), 2.35 (s, 3 H),
2.22−2.10 (m, 2 H), 1.87 (s, 3 H), 1.17 (s, 9 H). MS
(C30H32FN3O4): m/z 518 (M + H)+.
2-(2-(4-(Benzyloxy)phenyl)-7-(8-fluoro-5-methylchroman-6-
yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-tert-butoxyace-
tic Acid, TFA Salt ((S,S and R,R)-21). The title compound was
prepared from methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-
a]pyrimidin-6-yl)-2-tert-butoxyacetate in a manner similar to that
described for compound (S,S and R,R)-20. 1H NMR (400 MHz,
CDCl3) δ (ppm): 7.76 (d, J = 8.8 Hz, 2H), 7.47−7.32 (m, 5H),
7.04−6.95 (m, 3H), 6.91 (d, J = 10.5 Hz, 1H), 5.11 (d, J = 2.0 Hz,
3H), 4.44−4.25 (m, 2H), 2.92−2.59 (m, 5H), 2.28−2.10 (m, 2H),
1.89 (s, 3H), 1.22 (s, 9H). MS (C36H36FN3O5): m/z 610 (M + H)+.
2-(2-(3-(Benzyloxy)phenyl)-7-(8-fluoro-5-methylchroman-6-
yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-tert-butoxyace-
tic Acid, TFA Salt ((S,S and R,R)-22). The title compound was
prepared from methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-
a]pyrimidin-6-yl)-2-tert-butoxyacetate in a manner similar to that
described for compound (S,S and R,R)-20. 1H NMR (500 MHz,
CDCl3) δ (ppm): 7.48−7.27 (m, 8H), 6.96 (dd, J = 8.2, 1.8 Hz, 1H),
6.93−6.88 (m, 2H), 5.08 (s, 3H), 4.46−4.12 (m, 2H), 2.92−2.73 (m,
5H), 2.26−2.08 (m, 2H), 1.91 (s, 3H), 1.20 (s, 9H). MS
(C36H36FN3O5): m/z 610 (M + H)+.
2-tert-Butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-
methyl-2-(3-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-6-yl)-
acetic Acid, TFA Salt ((S,S and R,R)-23). The title compound was
prepared from methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-
a]pyrimidin-6-yl)-2-tert-butoxyacetate in a manner similar to that
described for (S,S and R,R)-20. 1H NMR (400 MHz, CDCl3) δ
(ppm): 7.62−7.49 (m, 2H), 7.41−7.31 (m, 3H), 7.17−6.95 (m, 5H),
6.90 (d, J = 10.8 Hz, 1H), 5.12 (s, 1H), 4.50−4.22 (m, 2H), 2.89−
2.66 (m, 5H), 2.17 (dd, J = 6.0, 4.0 Hz, 2H), 1.90 (s, 3H), 1.28−1.09
(m, 9H). MS (C35H34FN3O5): m/z 596 (M + H)+.
2-(2-([1,1′-Biphenyl]-3-yl)-7-(8-fluoro-5-methylchroman-6-
yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)-
acetic Acid, TFA Salt ((S,S and R,R)-24). The title compound was
prepared from methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-
a]pyrimidin-6-yl)-2-tert-butoxyacetate in a manner similar to that
described for (S,S and R,R)-20. 1H NMR (500 MHz, CDCl3) δ
(ppm): 8.05−7.98 (m, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.65−7.58 (m,
2H), 7.55 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.5 Hz, 3H), 7.40−7.33 (m,
1H), 6.98−6.90 (m, 2H), 5.09 (s, 1H), 4.38−4.27 (m, 2H), 2.82−
2.66 (m, 5H), 2.15 (d, J = 6.1 Hz, 2H), 1.93 (s, 3H), 1.21 (s, 9H). MS
(C35H34FN3O4): m/z 580 (M + H)+.
L
J. Med. Chem. XXXX, XXX, XXX−XXX