Potent and Selective TGF-â Type I Receptor Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 18 4503
found, 305.0839. Analytical HPLC tR ) 1.64 min, 100% pure
(A), tR ) 1.88 min, 100% pure (B).
The following compounds were prepared using a similar
MS: calcd for C18H14N4S (M + H), 319.1017; found, 319.0985.
Analytical HPLC tR ) 1.77 min, 100% pure (A), tR ) 1.99 min,
100% pure (B).
procedure with appropriate ethanones.
5-(Naph th alen -1-yl)-4-(pyr idin -2-yl)- 1,3-th iazol-2-am in e
(9). Compound 32 (0.4 g, 1.62 mmol) was reacted as described
for 1 to afford 9 as a yellow solid (0.04 g, 8%); mp 179 °C. H
4-(P yr idin -3-yl)-5-(qu in olin -4-yl)-1,3-th iazol-2-am in e (2).
Compound 24 (0.52 g, 2.09 mmol) was reacted as described
for 1. The crude product was crystallized from EtOAc, to afford
2 as an orange solid (0.112 g, 17.6%); mp 232 °C. 1H NMR
(300 MHz, DMSO-d6): δ 8.73 (d, J ) 4.33 Hz, 1H), 8.24-8.21
(m, 1H), 8.14 (dd, J ) 4.71, 1.51 Hz, 1H), 7.91 (bd, J ) 8.48
Hz, 1H), 7.66-7.54 (m, 2H), 7.42-7.17 (m, 5H), 7.00 (dd, J )
7.92, 8.10 Hz, 1H). MS (ES) m/z 305 (M + H)+. HR-MS: calcd
for C17H12N4S (M + H), 305.0861; found, 305.0871. Analytical
HPLC tR ) 1.56 min, 100% pure (A), tR ) 1.85 min, 100% pure
(B).
1
NMR (200 MHz, CDCl3): δ 7.84 (bd, J ) 4.58 Hz, 1H), 7.82-
7.56 (m, 2H), 7.62-7.56 (m, 2H), 7.52 (dd, J ) 7.94, 7.32 Hz,
1H), 7.28 (m, 3H), 7.13 (dd, J ) 4.89, 4.89 Hz, 1H), 6.89 (dd,
J ) 4.89, 4.89 Hz, 1H), -NH2 not observed. MS (APCI) m/z
304 (M + H)+. HR-MS: calcd for C18H13N3S (M + H), 304.0908;
found, 304.0926. Analytical HPLC tR ) 2.33min, 100% pure
(B). Analytical HPLC tR ) 7.71min, 100% pure (C).
5-(1,8-Na p h th yr id in -4-yl)-4-(p yr id in -2-yl)-1,3-th ia zol-2-
a m in e (10). A solution of 4-methyl[1,8]- naphthyridine (21,
0.38 g, 2.64 mmol) and ethyl picolinate (0.4 g, 2.64 mmol) in
anhydrous THF (20 mL) was stirred under nitrogen and cooled
to -78 °C. Potassium bis(trimethylsilyl)amide (0.5 M solution
in toluene, 10.5 mL, 5.27 mmol) was added dropwise over 10
min. The reaction mixture was then stirred at -78 °C for 1 h
and allowed to cool to room temperature for 18 h. Saturated
aqueous ammonium chloride was added, and the mixture was
partitioned between EtOAc and water. The aqueous phase was
extracted with EtOAc. The organic layers were combined,
washed with water, dried over sodium sulfate, and evaporated
to give the 2-(1,8-naphthyridin-4-yl)-1-(2-pyridinyl)ethanone
(30, 0.34 g, 0.56 mmol). Compound 30 was reacted immediately
with bromine (0.035 mL, 0.68 mmol) in dioxane (10 mL)
without further purification. The brown suspension was stirred
at room temperature for 1 h and then evaporated to dryness.
Thiourea (0.093 g, 1.45 mmol) and ethanol (10 mL) were added,
and the mixture was heated at 78 °C for 3 h. The reaction
mixture was cooled to room temperature and treated with
aqueous ammonia (0.88, 10 mL). After evaporation to dryness,
the crude product was purified by flash column chromatogra-
phy on silica gel eluting with chloroform/methanol/aqueous
ammonia 100/8/1 and crystallized from ethanol/diethyl ether
to afford 10 as a brown solid (0.085 g, 50%). 1H NMR (400
MHz, DMSO-d6): δ 9.04 (d, J ) 4.5 Hz, 1H), 8.99 (dd, J )
7.53, 3.52 Hz, 1H), 8.10 (d, J ) 8.03 Hz, 1H), 7.91 (d, J ) 7.53
Hz, 1H), 7.85 (d, J ) 3.52 Hz, 1H), 7.80-7.72 (m, 1H), 7.56 (d,
J ) 4 Hz, 1H), 7.47 (bs, 2H), 7.41 (dd, J ) 7.53, 3.52 Hz, 1H),
7.10-7.08 (m, 1H). MS (APCI) m/z 306 (MH+). HR-MS: calcd
for C16H11N5S (M + H), 306.0813; found, 306.0795. Analytical
HPLC tR ) 1.11 min, 100% pure (A), tR ) 1.53 min, 100% pure
(B).
5′-(Qu in olin -4-yl)-2,4′-bi-1,3-th ia zol-2′-a m in e (3). Com-
pound 31 (0.254 g, 1 mmol) was reacted as described for 1 to
1
afford 3 as yellow crystals (0.08 g, 26%); mp 238 °C. H NMR
(250 MHz, CDCl3): δ 8.88 (d, J ) 4.33 Hz, 1H), 8.04 (d, J )
8.48 Hz, 1H), 7.74 (d, J ) 7.92 Hz, 1H), 7.69 (d, J ) 8.48 Hz,
1H), 7.60-7.51 (4H, m), 7.47 (dd, J ) 7.91, 7.15 Hz, 1H), 7.37
(d, J ) 3.20 Hz, 1H). MS (APCI) m/z 311 (M + H)+. HR-MS:
calcd for C15H10N4S2 (M + H), 311.0425; found, 311.0399.
Analytical HPLC tR ) 1.69 min, 100% pure (A), tR ) 2.18 min,
100% pure (B).
4-(2-F lu or op h e n yl)-5-(q u in olin -4-yl)-1,3-t h ia zol-2-
a m in e (4). Compound 25 (0.53 g, 2 mmol) was reacted as
described for 1 to afford 4 as a yellow powder (0.14 g, 22%);
1
mp 265-270 °C. H NMR (250 MHz, DMSO-d6): δ 8.87 (d, J
) 4.58 Hz, 1H), 8.10 (d, J ) 8.24 Hz, 1H), 8.02 (d, J ) 8.54
Hz, 1H), 7.80 (dd, J ) 8.24, 8.24 Hz, 1H), 7.66-7.48 (m, 4H),
7.37 (d, J ) 4.58 Hz, 1H), 7.35-7.27 (m, 1H), 7.19 (dd, J )
7.33, 7.63 Hz 1H), 7.04 (dd, J ) 8.24, 8.24 Hz, 1H). MS (APCI)
m/z 322 (M + H)+. HR-MS: calcd for C18H12FN3S (M + H),
322.0814; found, 322.0829. Analytical HPLC tR ) 1.96 min,
100% pure (A), tR ) 2.14 min, 100% pure (B).
4-[2-(Met h oxy)p h en yl]-5-(q u in olin -4-yl)-1,3-t h ia zol-2-
a m in e (5). Compound 26 (0.483 g, 1.7 mmol) was reacted as
described for 1 to afford 5 as a pale yellow powder (0.04 g,
1
7%); mp 222-225 °C. H NMR (300 MHz, CDCl3): δ 8.65 (d,
J ) 4.58 Hz, 1H), 8.04 (d, J ) 8.54 Hz, 1H), 7.97 (d, J ) 8.54
Hz, 1H), 7.59 (dd, J ) 7.02, 7.02 Hz, 1H), 7.40-7.27 (m, 2H),
7.11 (d, J ) 4.58 Hz, 1H), 7.09-7.04 (m, 1H), 6.76 (dd, J )
7.33, 7.33 Hz, 1H), 6.52 (d, J ) 8.24 Hz, 1H), 5.42 (bs, 2H),
2.99 (s, 3H). MS (APCI) m/z 334 (M + H)+. HR-MS: calcd for
C
19H15N3OS (M + H), 334.1014; found, 334.0985. Analytical
HPLC tR ) 1.93 min, 100% pure (A), tR ) 2.10 min, 100% pure
(B).
5-(1,5-Na p h th yr id in -2-yl)-4-(p yr id in -2-yl)-1,3-th ia zol-2-
a m in e (11). A solution of 41 (6.63 g, 26.6 mmol) in dioxane
(300 mL) was treated with bromine (1.65 mL, 31.9 mmol). The
orange suspension was stirred at room temperature for 1 h
and then concentrated. The residue was dissolved in ethanol
(500 mL), thiourea (2.22 g, 2.93 mmol) was added, and the
reaction mixture was heated at 78 °C for 4 h. The reaction
was cooled to room temperature, and an aqueous solution of
ammonia (0.88 M, 50 mL) was added with stirring. The
mixture was evaporated, and the residue was dissolved in CH2-
Cl2 and washed with water (300 mL). The organic phase was
extracted with 1 N hydrochloric acid (300 mL, 2 × 200 mL).
The aqueous layers were basified with aqueous sodium
hydroxide 35% (800 mL) and extracted with CH2Cl2. The
organic phase was dried over sodium sulfate and evaporated
to give the crude product as a brown powder. This powder was
crystallized from acetonitrile to afford 11 (1.26 g, 16%) as
4-(5-Ch lor o-p yr id in -2-yl)-5-(qu in olin -4-yl)-1,3-th ia zol-
2-a m in e (6). Compound 27 (0.296 g, 1.05 mmol) was reacted
as described for 1 to afford 6 as a yellow solid (0.225 g, 63%).
1H NMR (400 MHz, DMSO-d6): δ 8.84 (d, J ) 4.02 Hz, 1H),
8.02 (d, J ) 8.03 Hz, 1H), 7.97-7.94 (m, 1H), 7.90-7.87 (m,
2H), 7.75-7.68 (m, 2H), 7.47-7.41 (m, 4H). MS (APCI) m/z
339 (M + H)+. HR-MS: calcd for C17H11ClN4S (M + H),
339.0471; found, 339.0474. Analytical HPLC tR ) 2.03 min,
100% pure (A), tR ) 2.17 min, 100% pure (B).
4-(4-Ch lor o-p yr id in -2-yl)-5-(qu in olin -4-yl)-1,3-th ia zol-
2-a m in e (7). Compound 28 (0.25 g, 0.88 mmol) was reacted
as described for 1 to afford 7 as brown crystals (0.14 g, 47%).
1H NMR (400 MHz, DMSO-d6): δ 8.86 (d, J ) 4.52 Hz, 1H),
8.03 (d, J ) 8.53 Hz, 1H), 7.94 (d, J ) 2 Hz, 1H), 7.88 (d, J )
5.52 Hz, 1H), 7.75-7.68 (m, 2H), 7.50-7.44 (m, 4H), 7.22 (dd,
J ) 5.52, 2 Hz, 1H). MS (APCI) m/z 339 (M + H)+. HR-MS:
calcd for C17H11ClN4S (M + H), 339.0471; found, 339.0462.
Analytical HPLC tR ) 1.88 min, 100% pure (A), tR ) 2.17 min,
100% pure (B).
1
yellow crystals; mp 114 °C. H NMR (400 MHz, DMSO-d6): δ
8.87 (dd, J ) 4.04 Hz, 1.51, 1H,), 8.53 (bd, J ) 4.54 Hz, 1H),
8.28 (bd, J ) 8.09 Hz, 1H), 8.08 (d, J ) 9.10 Hz, 1H), 7.94 (dd,
J ) 7.58, 1.51 Hz, 1H), 7.80 (bd, J ) 8.09 Hz, 1H), 7.72 (dd, J
) 4.04, 8.59 Hz, 1H), 7.56 (bs, 2H), 7.50 (d, J ) 8.59 Hz, 1H),
7.44 (dd, J ) 5.06, 6.67 Hz, 1H). MS (APCI) m/z 306 (M +
H)+. HR-MS: calcd for C16H11N5S (M + H), 306.0813; found,
306.0800. Analytical HPLC tR ) 1.77 min, 100% pure (A), tR
) 1.78 min, 100% pure (B).
4-(5-Meth yl-p yr id in -2-yl)-5-(qu in olin -4-yl)-1,3-th ia zol-
2-a m in e (8). Compound 29 (0.3 g, 1.15 mmol) was reacted as
1
described for 1 to afford 8 as a yellow solid (0.18 g, 49%). H
NMR (400 MHz, DMSO-d6): δ 8.68 (d, J ) 4.52 Hz, 1H), 7.87
(d, J ) 8.03 Hz, 1H), 7.64-7.56 (m, 3H), 7.54 (dd, J ) 7.03,
7.03 Hz, 1H), 7.40 (d, J ) 8.03 Hz, 1H), 7.30-7.23 (m, 2H),
7.20 (bs, 2H), 2.07 (bs, 3H). MS (APCI) m/z 319 (M + H)+. HR-
4-(P yr id in -2-yl)- 5-(qu in olin -2-yl)-1,3-th ia zol-2-a m in e
(12). Compound 47 (0.5 g, 2.02 mmol) was reacted as described