Pyrazine-Pyridine Biheteroaryls as VEGFR-2 Inhibitors
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4901
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8.73 (brs, 1 H), 7.44-7.27 (m, 1 H), 7.07-6.91 (m, 3 H), 1.50
(s, 9 H); MS (ES) m/z: 409 (M - H+).
the preparation of 6 gave 18: 50% yield; H NMR (300 MHz,
CDCl3) δ 9.28 (s, 1 H), 8.74 (s, 1 H), 8.59 (d, J ) 3 Hz, 1 H),
8.47 (d, J ) 3.0 Hz, 1 H), 8.30 (brs, 1 H), 7.49 (dd, J ) 9.0, 3.0
Hz, 1 H), 7.40-7.25 (m, 3 H), 6.98 (s, 1 H), 1.54 (s, 9 H), 1.47
(s, 9 H); MS (ES) m/z: 498 (M + H+).
[6-(5-tert-Butoxycarbonylamino-pyridin-3-yl)-pyrazin-
2-yl]-(3-fluoro-phenyl)-carbamic Acid tert-Butyl Ester 10.
Replacing 5 with 9 and following the same procedure as in
the preparation of 6 gave 10 as a yellowish gum: 31% yield;
1H NMR (300 MHz, CDCl3) δ 8.99 (s, 1 H), 8.80 (s, 1 H), 8.68
(d, J ) 1.9 Hz, 1 H), 8.46 (d, J ) 2.5 Hz, 1 H), 8.38 (brs, 1 H),
7.41-7.27 (m, 1 H), 7.06-7.01 (m, 3 H), 6.58 (brs, 1 H), 1.54
(s, 9 H), 1.49 (s, 9 H); FAB-HRMS (M + H+) calcd. for
C25H29N5O4F 482.2204, found 482.2204.
3-{5-[6-(2-Chloro-phenylamino)-pyrazin-2-yl]-pyridin-
3-ylamino}-propan-1-ol 19. Replacing 6 with 18 and follow-
ing the same procedure as in the preparation of 7 gave 19 as
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a solid: 61% yield; H NMR (300 MHz, CD3OD) δ 8.45 (s, 1
H), 8.36 (s, 1 H), 8.22 (s, 1 H), 8.17 (dd, J ) 9.0, 3.0 Hz, 1 H),
7.97 (s, 1 H), 7.59 (s, 1 H), 7.47 (dd, J ) 9.0, 3.0 Hz, 1 H), 7.34
(dd, J ) 6.0, 6.0, 3.0 Hz, 1 H), 7.10 (ddd, J ) 6.0, 6.0, 3.0 Hz,
1 H), 3.70 (t, J ) 6.0 Hz, 2 H), 3.27 (t, J ) 6.0 Hz, 2 H), 1.87
(t, J ) 6.0 Hz, 2 H); MS (ES) m/z: 356 (M + H+).
3-[[5-[6-[(3-Fluorophenyl)amino]pyrazinyl]-3-pyridinyl]-
amino]-1-propanol 11. Replacing 6 with 10 and following
the same procedure as in the preparation of 7 gave 11 as a
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yellow solid: 27% yield; H NMR (300 MHz, CD3OD) δ 8.46
General Procedure for the Synthesis of 20, 24, and 28.
(3-Chloro-phenyl)-{6-[5-(3-pyridin-4-yl-propylamino)-pyridin-
3-yl]-pyrazin-2-yl}-amine 20. A mixture of 6 (0.1 g, 0.2 mmol),
4-(3-chloropropyl)pyridine35 (0.047 g, 0.3 mmol), and Cs2CO3
(0.197 g, 0.6 mmol) in DMF (4 mL) was stirred at 70 °C under
nitrogen for 20 h. The reaction mixture was diluted with water,
extracted with ether (3×), dried (Na2SO4), and concentrated.
The product was purified by column chromatography (EtOAc/
MeOH as solvent) to give 0.074 g of product as an oil. The oil
was dissolved in TFA (2.0 mL) and stirred at 20 °C for 2 h
before concentrated. Ammonium hydroxide solution was added
to the residue until the pH was about 10-11. The aqueous
layer was extracted with CH2Cl2, dried (Na2SO4), and concen-
trated. Product was purified by column chromatography (CH2-
Cl2/MeOH as solvent) to give 0.045 g (91%) of 20 as a yellow
solid: 1H NMR (300 MHz, CD3OD) δ 8.42 (m, 4 H), 8.12 (s, 2
H), 7.99 (s, 1 H), 7.65 (s, 1 H), 7.48 (m, 1 H), 7.34 (s, 2 H), 7.25
(t, J ) 8.0 Hz, 1 H), 6.97 (d, J ) 6.7 Hz, 1 H), 3.30 (m, 2 H),
2.83 (m, 2 H), 2.03 (m, 2 H); MS (ES) m/z: 417 (M + H+); FAB-
HRMS (M + H+) calcd. for C23H22ClN6 417.1594, found
417.1605.
5-[6-(4-Chloro-phenylamino)-pyrazin-2-yl]-nicotinic
Acid Ethyl Ester 21. Replacing 3-chloroaniline with 4-
chloroaniline and following the same procedure as in the
preparation of 4 gave 21 as a yellow solid: 56% yield; 1H NMR
(300 MHz, CDCl3) δ 9.40 (d, J ) 2.1 Hz, 1 H), 9.29 (d, J ) 1.9
Hz, 1 H), 8.87 (t, J ) 2.0 Hz, 1 H), 8.55 (s, 1 H), 8.22 (s, 1 H),
7.52 (d, J ) 8.7 Hz, 2 H), 7.35 (d, J ) 8.7 Hz, 2 H), 6.71 (s, 1
H), 4.47 (q, J ) 7.1 Hz, 2 H), 1.44 (t, J ) 7.1 Hz, 3 H); MS
(ES) m/z: 355 (M + H+).
5-{6-[tert-Butoxycarbonyl-(4-chloro-phenyl)-amino]-
pyrazin-2-yl}-nicotinic Acid 22. Replacing 4 with 21 and
following the same procedure as in the preparation of 5 gave
22 as a yellow solid: 94% yield; MS (ES) m/z: 427 (M + H+).
[6-(5-tert-Butoxycarbonylamino-pyridin-3-yl)-pyrazin-
2-yl]-(4-chloro-phenyl)-carbamic Acid tert-Butyl Ester
23. Replacing 5 with 22 and following the same procedure as
in the preparation of 6 gave 23 as a foam: 55% yield: 1H NMR
(300 MHz, CDCl3) δ 9.02 (s, 1 H), 8.78 (s, 1 H), 8.68 (d, J )
1.8 Hz, 1 H), 8.44 (d, J ) 2.4 Hz, 2 H), 7.38 (d, J ) 8.7 Hz, 2
H), 7.22 (d, J ) 8.7 Hz, 2 H), 6.56 (brs, 1 H), 1.55 (s, 9 H), 1.48
(s, 9 H); MS (ES) m/z: 498 (M + H+).
(s, 1 H), 8.43 (d, J ) 1.8 Hz, 1 H), 8.13 (brs, 1 H), 8.01 (d, J )
2.7 Hz, 1 H), 7.90 (dt, J ) 12.1, 2.1 Hz, 1 H), 7.68 (t, J ) 2.1
Hz, 1 H), 7.42-7.28 (m, 2 H), 6.73 (t, J ) 8.3 Hz, 1 H), 3.72 (t,
J ) 6.2 Hz, 2 H), 3.31 (m, 2 H), 1.91 (m, 2 H); FAB-HRMS (M
+ H+) calcd. for C18H19N5OF 340.1574, found 340.1586.
5-[6-(3-Methoxy-phenylamino)-pyrazin-2-yl]-nico-
tinic Acid Ethyl Ester 12. Replacing 3-chloroaniline with
3-methoxyaniline and following the same procedure as in the
preparation of 4 gave 12 as a yellow solid: 65% yield; 1H NMR
(300 MHz, CDCl3) δ 9.42 (d, J ) 2.1 Hz, 1 H), 9.28 (d, J ) 2.0
Hz, 1 H), 8.89 (t, J ) 2.1 Hz, 1 H), 8.53 (s, 1 H), 8.27 (s, 1 H),
7.3-7.27 (m, 2 H), 7.05 (dd, J ) 7.9, 1.3 Hz, 1 H), 6.78 (brs, 1
H), 6.69 (brd, J ) 7.6 Hz, 1 H), 4.48 (q, J ) 7.1 Hz, 2 H), 3.85
(s, 3 H), 1.56 (t, J ) 7.1 Hz, 3 H); Anal. (C19H18N4O3‚0.5H2O)
C, H, N.
5-{6-[tert-Butoxycarbonyl-(3-methoxy-phenyl)-amino]-
pyrazin-2-yl}-nicotinic Acid 13. Replacing 4 with 12 and
following the same procedure as in the preparation of 5 gave
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13 as a yellow solid: 71% yield; H NMR (300 MHz, CD3OD)
δ 9.16 (d, J ) 2.2 Hz, 1 H), 9.11 (d, J ) 1.9 Hz, 1 H), 9.04 (s,
1 H), 8.98 (s, 1 H), 8.82 (t, J ) 2.1 Hz, 1 H), 7.35 (t, J ) 8.0
Hz, 1 H), 6.96-6.85 (m, 3 H), 3.81 (s, 3 H), 1.48 (s, 9 H); MS
(ES) m/z: 421 (M - H+). Anal. (C22H22N405‚0.3 H2O) C, H, N.
[6-(5-tert-Butoxycarbonylamino-pyridin-3-yl)-pyrazin-
2-yl]-(3-methoxy-phenyl)-carbamic Acid tert-Butyl Ester
14. Replacing 5 with 13 and following the same procedure as
in the preparation of 6 gave 14 as a yellowish gum: 75% yield;
1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1 H), 8.78 (s, 1 H), 8.71
(d, J ) 1.9 Hz, 1 H), 8.49 (d, J ) 2.5 Hz, 1 H), 8.38 (brs, 1 H),
7.31 (t, J ) 8.2 Hz, 1 H), 6.87-6.82 (m, 3 H), 6.63 (brs, 1 H),
3.81 (s, 3 H), 1.54 (s, 9 H), 1.49 (s, 9 H); MS (ES) m/z: 494 (M
+ H+).
3-[[5-[6-[(3-Methoxyphenyl)amino]pyrazinyl]-3-pyri-
dinyl]amino]-1-propanol 15. Replacing 6 with 14 and fol-
lowing the same procedure as in the preparation of 7 gave 15
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as a yellow solid: 10% yield; H NMR (300 MHz, CD3OD) δ
8.44 (d, J ) 1.6 Hz, 1 H), 8.39 (s, 1 H), 8.10 (s, 1 H), 8.00 (d,
J ) 2.8 Hz, 1 H), 7.67 (brs, 1 H), 7.65 (brs, 1 H), 7.23-7.20
(m, 2 H), 6.62-6.58 (m, 1 H), 3.81 (s, 3 H), 3.72 (t, J ) 6.2 Hz,
2 H) 3.31 (m, 2 H), 1.90 (m, 2 H); Anal. (C19H21N502‚0.5 H2O)
C, H, N.
5-[6-(2-Chloro-phenylamino)-pyrazin-2-yl]-nicotinic
Acid Ethyl Ester 16. Replacing 3-chloroaniline with 2-chlo-
roaniline and following the same procedure as in the prepara-
(4-Chloro-phenyl)-{6-[5-(3-pyridin-4-yl-propylamino)-
pyridin-3-yl]-pyrazin-2-yl}-amine 24. Replacing 6 with 23
and following the same procedure as in the preparation of 20
gave 24 as a light yellow solid: 79% yield; 1H NMR (300 MHz,
CD3OD) δ 8.39 (m, 4 H), 8.10 (s, 1 H), 7.98 (s, 1 H), 7.77 (m, 2
H), 7.61 (s, 1 H), 7.33 (d, J ) 6.1 Hz, 2 H), 7.27 (dd, J ) 6.9,
2.1 Hz, 2 H), 3.25 (t, J ) 6.8 Hz, 2 H), 2.84 (t, J ) 7.6 Hz, 2
H), 2.04 (m, 2 H); MS (ES) m/z: 417 (M + H+); FAB-HRMS
(M + H+) calcd. for C23H23ClN6 417.1594, found 417.1588.
5-[6-(3,4-Dichloro-phenylamino)-pyrazin-2-yl]-nico-
tinic Acid Ethyl Ester 25. Replacing 3-chloroaniline with
3,4-dichloroaniline and following the same procedure as in the
preparation of 4 gave 25 as a yellow solid: 24% yield; 1H NMR
(300 MHz, CDCl3) δ 9.15 (d, J ) 1.9 Hz, 1 H), 9.06 (d, J ) 2.1
Hz, 1 H), 8.53 (s, 1 H), 8.45 (s, 1 H), 8.07 (m, 1 H), 7.50 (m, 1
H), 7.40 (m, 1 H), 7.21 (dd, J ) 8.7, 1.5 Hz, 1 H), 4.45 (q, J )
7.1 Hz, 2 H), 1.44 (t, J ) 7.1 Hz, 3 H); MS (ES) m/z: 389 (M
+ H+).
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tion of 4 gave 16 as a solid: 69% yield; H NMR (300 MHz,
CDCl3) δ 9.44 (d, J ) 3.0 Hz, 1 H), 9.30 (d, J ) 3.0 Hz, 1 H),
8.89 (s, 1 H), 8.60 (s, 1 H), 8.37 (d, J ) 9.0, 1 H), 8.29 (s, 1 H),
7.47 (d, J ) 9.0, 1 H), 7.35 (dd, J ) 9.0, 6.0 Hz, 1 H), 7.14 (brs,
1 H), 7.06 (dd, J ) 9.0, 6.0 Hz, 1 H), 4.48 (q, J ) 6.0 Hz, 2 H),
1.46 (t, J ) 6.0 Hz, 3 H); MS (ES) m/z: 355 (M + H+).
5-{6-[tert-Butoxycarbonyl-(2-chloro-phenyl)-amino]-
pyrazin-2-yl}-nicotinic Acid 17. Replacing 4 with 16 and
following the same procedure as in the preparation of 5 gave
17 as a solid: 64% yield as a mixture of two inseparable
compounds (17 and des-Boc-17) in 7:3 ratio; MS (ES) m/z:
427 (M + H+).
[6-(5-tert-Butoxycarbonylamino-pyridin-3-yl)-pyrazin-
2-yl]-(2-chloro-phenyl)-carbamic acid tert-butyl Ester 18.
Replacing 5 with 17 and following the same procedure as in