Journal of Medicinal Chemistry
Article
7.73−7.46 (m, 5H), 7.25 (t, J = 7.4, 1H), 3.89 (s, 2H), 3.78 (s, 2H),
2.49 (s, 3H). HRMS calculated for C22H19F3N4O, 412.1511; found m/
z (M + H)+, 413.1576. HPLC purity: 96.6%.
3-Methyl-1-p-tolyl-5-((3-(trifluoromethyl)benzylamino)methyl)-
1H-pyrazolo[3,4-b]pyridin-6(7H)-one (11). 1H NMR (400 MHz,
DMSO-d6) δ ppm 8.14−8.05 (m, 2H), 7.99 (s, 1H), 7.75 (s, 1H), 7.69
(d, J = 7.4 Hz, 1H), 7.60 (dt, J = 15.1, 7.7 Hz, 2H), 7.30 (d, J = 8.2 Hz,
2H), 3.88 (s, 2H), 3.77 (s, 2H), 2.47 (s, 3H), 2.35 (s, 3H). HRMS
calculated for C23H21F3N4O, 426.1667; found m/z (M + H)+,
427.1735. HPLC purity: 99.5%.
3-Methyl-1-(pyridin-2-yl)-5-((3-(trifluoromethyl)benzylamino)-
methyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (12). 1H NMR (400
MHz, DMSO-d6) δ ppm 8.62−8.49 (m, 1H), 8.02 (td, J = 7.9, 2.0 Hz,
1H), 7.86 (t, J = 4.1 Hz, 2H), 7.73 (s, 1H), 7.68 (d, J = 7.1 Hz, 1H),
7.63−7.50 (m, 2H), 7.34 (dd, J = 7.3, 5.0 Hz, 1H), 3.84 (s, 2H), 3.55
(s, 2H), 2.43 (s, 3H). HRMS calculated for C21H18F3N5O, 413.1463;
found m/z (M + H)+, 414.1538. HPLC purity: 99.5%.
1,3-Dimethyl-5-((3-(trifluoromethyl)benzylamino)methyl)-1H-
pyrazolo[3,4-b]pyridin-6(7H)-one (13). 1H NMR (400 MHz, DMSO-
d6) δ ppm 7.86 (d, J = 7.3 Hz, 2H), 7.76 (d, J = 7.6 Hz, 1H), 7.71 (d, J
= 7.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 4.12 (s, 2H), 3.84 (s, 2H), 3.78
(s, 3H), 2.30 (s, 3H). HRMS calculated for C17H17F3N4O, 350.1354;
found m/z (M + H)+, 351.1424. HPLC purity: 98.6%.
3-Cyclopropyl-1-phenyl-5-((3-(trifluoromethyl)benzylamino)-
methyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (14). 1H NMR (400
MHz, DMSO-d6) δ ppm 8.26−8.14 (m, 2H), 8.03 (s, 1H), 7.76 (s,
1H), 7.69 (d, J = 7.4 Hz, 1H), 7.66−7.53 (m, 2H), 7.53−7.42 (m,
2H), 7.30−7.20 (m, 1H), 3.89 (s, 2H), 3.78 (s, 2H), 2.27 (m, 1H),
1.19−0.89 (m, 4H). HRMS calculated for C24H21F3N4O, 438.1667;
found m/z (M + H)+, 439.1739. HPLC purity: 99.5%.
3-Cyclopropyl-1-phenyl-5-(((6-(trifluoromethyl)pyridin-2-yl)-
methylamino)methyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (15).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (d, J = 8.0 Hz, 2H),
8.06 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.7 Hz,
1H), 7.48 (t, J = 7.9 Hz, 2H), 7.24 (t, J = 7.5 Hz, 1H), 3.96 (s, 2H),
3.80 (s, 2H), 2.26 (p, J = 6.9 Hz, 1H), 1.14−0.93 (m, 4H). HRMS
calculated for C23H20F3N5O, 439.1620; found m/z (M + H)+, 440.169.
HPLC purity: 98.0%.
3-Cyclopropyl-5-((2-fluoro-5-(trifluoromethyl)benzylamino)-
methyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (16). 1H
NMR (400 MHz, DMSO-d6) δ ppm 8.17 (d, J = 8.1 Hz, 2H), 8.05
(s, 1H), 7.97−7.87 (m, 1H), 7.70 (t, J = 6.7 Hz, 1H), 7.48 (t, J = 7.9
Hz, 2H), 7.41 (t, J = 9.2 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 3.87 (s,
2H), 3.77 (s, 2H), 2.26 (m, 1H), 1.04 (d, J = 8.4 Hz, 4H). HRMS
calculated for C24H20F4N4O, 456.1573; m/z (M + H)+, 457.1644.
HPLC purity: 97.3%.
3-Cyclopropyl-5-((2-fluoro-3-(trifluoromethyl)benzylamino)-
methyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (17). 1H
NMR (400 MHz, DMSO-d6) δ ppm 8.28 (d, J = 7.8 Hz, 2H), 7.83
(s, 1H), 7.67 (dd, J = 16.1, 8.3 Hz, 2H), 7.54−7.28 (m, 3H), 7.15 (s,
1H), 3.82 (s, 2H), 3.67 (s, 2H), 2.17 (bs, 1H), 0.99 (d, J = 6.7 Hz,
4H). HRMS calculated for C24H20F4N4O, 456.1573; found m/z (M +
H)+, 457.1648. HPLC purity: 95.1%.
3-Cyclopropyl-5-(((3-methyl-6-(trifluoromethyl)pyridin-2-yl)-
methylamino)methyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-
one (18). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (d, J = 7.9 Hz,
2H), 8.02 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H),
7.49 (t, J = 7.8 Hz, 2H), 7.32−7.16 (m, 1H), 3.97 (s, 2H), 3.89 (s,
2H), 2.42 (s, 3H), 2.25 (m, 1H), 1.04 (d, J = 7.1 Hz, 4H). HRMS
calculated for C24H22F3N5O, 453.1776; found m/z (M + H)+,
454.1848. HPLC purity: 94.6%.
3-Cyclopropyl-5-((2-methyl-5-(trifluoromethyl)benzylamino)-
methyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (19). 1H
NMR (400 MHz, DMSO-d6) δ ppm 8.19 (d, J = 8.0 Hz, 2H), 8.05
(s, 1H), 7.80−7.65 (m, 1H), 7.50 (qd, J = 7.3, 1.9 Hz, 3H), 7.40 (d, J =
7.9 Hz, 1H), 7.24 (t, J = 7.3 Hz, 1H), 3.84 (d, J = 4.6 Hz, 4H), 2.37 (s,
3H), 2.31−2.13 (m, 1H), 1.14−0.92 (m, 4H). HRMS calculated for
C25H23F3N4O, 452.1824; found m/z (M + H)+, 453.189. HPLC
purity: 99.4%.
MHz, DMSO-d6) δ ppm 8.23 (d, J = 7.91 Hz, 2H), 7.98 (s, 1H), 7.72
(s, 1H), 7.33−7.56 (m, 4H), 7.16−7.30 (m, 1H), 3.82 (s, 4H), 2.47 (s,
3H), 2.36 (s, 3H), 1.90 (s, 1H). HRMS calculated for C23H21F3N4O:,
426.1667; found m/z (M + H)+, 427.1736. HPLC purity: 99.7%.
3-Isopropyl-5-((2-methyl-5-(trifluoromethyl)benzylamino)-
methyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (21). 1H
NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J = 8.0 Hz, 2H), 8.12
(s, 1H), 7.74 (s, 1H), 7.51 (t, J = 7.9 Hz, 3H), 7.40 (d, J = 7.9 Hz,
1H), 7.26 (t, J = 7.3 Hz, 1H), 3.84 (d, J = 8.4 Hz, 4H), 3.38−3.22 (m,
1H), 2.37 (s, 3H), 1.40 (d, J = 6.9 Hz, 6H). HRMS calculated for
C25H25F3N4O, 454.1980; found m/z (M + H)+, 455.205. HPLC
purity: 97.5%.
3-Methyl-5-((methyl(3-(trifluoromethyl)benzyl)amino)methyl)-1-
phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (22). 1H NMR (400
MHz, DMSO-d6) δ ppm 8.22 (d, J = 7.9 Hz, 2H), 8.06 (s, 1H), 7.77−
7.66 (m, 2H), 7.66−7.56 (m, 2H), 7.55−7.46 (m, 2H), 7.26 (tt, J =
7.3, 1.2 Hz, 1H), 3.73 (s, 2H), 3.66 (s, 2H), 2.20 (s, 3H). HRMS
calculated for C23H21F3N4O, 426.1667; found m/z (M + H)+,
427.1744. HPLC purity: 98.3%.
3-Methyl-1-phenyl-5-((7-(trifluoromethyl)-3,4-dihydroisoquino-
lin-2(1H)-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (23). 1H
NMR (400 MHz, DMSO-d6) δ ppm 8.22 (bs, 2H), 8.08 (s, 1H),
7.57−7.43 (m, 4H), 7.37 (d, J = 7.9 Hz, 1H), 7.27 (dd, J = 8.1, 6.6 Hz,
1H), 3.77 (s, 4H), 2.95 (d, J = 5.9 Hz, 2H), 2.84 (t, J = 5.9 Hz, 2H),
2.51 (s, 3H). HRMS calculated for C24H21F3N4O, 438.1667; found m/
z (M + H)+, 439.1738. HPLC purity: 98.6%.
3,7-Dimethyl-1-phenyl-5-((3-(trifluoromethyl)benzylamino)-
methyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (24). 1H NMR (400
MHz, DMSO-d6) δ ppm 7.83 (s, 1H), 7.74 (s, 1H), 7.69 (d, J = 7.3
Hz, 1H), 7.60 (dd, J = 7.3, 5.3 Hz, 2H), 7.55 (s, 5H), 3.87 (s, 2H),
3.59 (s, 2H), 3.08 (s, 3H), 2.37 (s, 3H). HRMS calculated for
C23H21F3N4O, 426.1667; found m/z (M + H)+, 427.1735. HPLC
purity: 99.1%.
1-(6-Methoxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-
1
yl)-N-(3-(trifluoromethyl)benzyl)methanamine (25). H NMR (400
MHz, DMSO-d6) δ ppm 8.27−8.29 (m, 2 H), 8.12 (s, 1 H), 7.75 (s, 1
H), 7.68 (d, J = 7.0 Hz, 1 H), 7.61−7.48 (m, 4 H), 7.26 (t, J = 7.3 Hz,
1 H), 4.01 (s, 3 H), 3.86 (s, 2 H), 3.72 (s, 2 H), 2.50−2.51 (m, 3H).
HRMS calculated for C23H21F3N4O, 426.1667; found m/z (M + H)+,
427.1736. HPLC purity: 99.5%.
3-Methyl-6-oxo-1-phenyl-N-(3-(trifluoromethyl)benzyl)-6,7-dihy-
dro-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (26). 1H NMR (400
MHz, DMSO-d6) δ ppm 8.22 (d, J = 8.1 Hz, 2H), 7.97 (s, 1H), 7.48
(t, J = 7.9 Hz, 3H), 7.37 (td, J = 8.1, 6.0 Hz, 1H), 7.22 (q, J = 7.0 Hz,
3H), 7.07 (td, J = 8.6, 2.6 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 2H), 2.47 (s,
3H). HRMS calculated for C22H17F3N4O2, 426.1304; found m/z (M +
H)+, 427.1365. HPLC purity: 99.9%.
ASSOCIATED CONTENT
* Supporting Information
■
S
Details of the synthesis of all compounds, biological assays,
results from analogue screening, and druggability assessment
from sitemap. This material is available free of charge via the
AUTHOR INFORMATION
Corresponding Author
*Phone: +91-80-23621212. Fax: +91-80-23621214. E-mail:
■
Author Contributions
M.P., S.R., and P.S.S. are responsible for medicinal chemistry
design and analyses. S.R. is responsible for synthetic chemistry.
K.N. performed synthesis of some of the pyrazolopyridones.
V.R. is responsible for design and analyses of microbiology
experiments. V.K.S. is responsible for design and analyses of
MoA and cytotoxicity studies. P.K., S.S., S.G., A.N., A.A., and
N.H. performed all the microbiological and MoA experiments.
V.H. and J. M. designed, performed, and analyzed the
3-Methyl-5-((2-methyl-5-(trifluoromethyl)benzylamino)methyl)-
1
1-phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (20). H NMR (300
I
dx.doi.org/10.1021/jm5002937 | J. Med. Chem. XXXX, XXX, XXX−XXX