Novel ureas for the treatment and prevention of cancer
A technology of compounds and metabolites, applied in the field of novel pentafluorothio-substituted urea derivatives
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[0180] Preparation of compounds of the present invention
[0181] Equations 1-2 show general methods for preparing the intermediates and compounds of the examples. These compounds can be prepared from starting materials known in the art or commercially available. Specific compounds are for illustrative purposes only.
[0182]
[0183] In Equation 1, SF 5 Substituted anilines can be converted to their isocyanate intermediates by treatment with triphosgene and base. The isocyanate intermediate can be reacted with the appropriate aniline to form the urea product.
[0184] formula 2
[0185]
[0186] In Equation 2, SF 5 Coupling of substituted anilines to chlorobenzoxazoles can be achieved by treatment with base. This intermediate can be further coupled with chloropyridine in the presence of a base to provide compounds of the invention.
[0187] Referring to the following examples, exemplary compounds of the invention have been synthesized by the methods described her...
Embodiment 1
[0188] Embodiment 1.N-Methyl-4-[4-({[3-(pentafluoro-λ 6 -thio)phenyl]carbamoyl}amino)phenoxy]pyridine-2-carboxamide
[0189] 3-(Pentafluoro-λ 6 A solution of -thio)aniline (0.9 g, 4 mmol) in 70 mL of anhydrous toluene was treated with 0.81 g of triphosgene, followed by the addition of 0.66 mL of triethylamine. The cloudy suspension was heated at 70°C for 1 hour and cooled to room temperature. The reaction mixture was then diluted with 40 mL of hexane, filtered, and concentrated to give the crude isocyanate. Dissolve the crude isocyanate in 40 mL of Cl 2 CH 2 CH 2 Cl 2 / toluene (1:1), treated with 0.85 g of 4-(4-aminophenoxy)-N-methylpicolinamide. The reaction mixture was stirred overnight and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient to 80% ethyl acetate / hexanes ( ) to give the desired product (1.3 g).
[0190] 1 H NMR (400MHz, DMSO-d 6 ):δ9.20(s,1H),8.98(s,1H),8.78(m,1H),8.53(d,1H),8.26(s,1H),7.45-7.62(m,5H),7...
Embodiment 2
[0191] Example 2.4-[3-fluoro-4-({[3-(pentafluoro-λ 6 -thio)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide
[0192] According to the same procedure as described in Example 1, the title compound was prepared from 3-(pentafluoro-λ 6 -thio)aniline and 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide as a white solid.
[0193] 1 H NMR (400MHz, DMSO-d 6 ):δ9.51(s,1H),8.82(m,1H),8.73(s,1H),8.53(d,1H),8.28(s,1H),8.18(t,1H),7.49-7.58( m,3H),7.42(d,1H),7.35(dd,1H),7.19(dd,1H),7.08(d,1H),2.80(d,3H).
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