Substituted heterocyclic compounds and uses thereof
A compound and heterocyclic group technology, applied in the field of new substituted heterocyclic compounds, can solve the problems of severe side effects in normal tissues and drug resistance in tumor cells
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[0360] For the preparation of pharmaceutical compositions of the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
[0361] A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can also be an encapsulating material.
[0362] In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
[0363] For preparing suppository compositions, a low melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted, and the active ingredient is dispersed t...
Embodiment 1
[0506] 5-Phenyl-2-ureido-thiophene-3-carboxylic acid (S)-azepan-3-ylamide
[0507] Methyl 2-amino-5-phenylthiophene-3-carboxylate. To a solution of phenylacetaldehyde (12.7 mL, 100 mmol) in DMF (150 mL) was added cyanomethyl acetate (8.9 mL, 100 mmol) and sulfur (3.2 g, 100 mmol), followed by the addition of diisopropylethylamine (Hunig's base, 17.4 mL, 100 mmol). The color of the resulting suspension immediately changed from dark yellow to brown, accompanied by an exotherm. The reaction mixture was stirred overnight at room temperature. The reaction was added slowly to water (-800 mL) with stirring. An off-white precipitate formed which was filtered off after a further 30 minutes of stirring. The resulting solid was purified by column chromatography (SiO 2 , 10-20% EtOAc / hexanes) to afford 23.2 g (100%) of the title compound as an off-white solid.
[0508] 1 H NMR (d 6 -DMSO, δ7.5, br s, 2H; δ7.45, m, 2H; δ7.33, m, 2H; δ7.24, s, 1H; δ7.18, m, 1H; 3H), LC / MS (APCI, ...
Embodiment 8
[0522] [3-((S)-3-Amino-azepane-1-carbonyl)-5-pyridin-4-yl-thiophen-2-yl]-urea 2-[(aminocarbonyl)amino]-5- Pyridin-4-ylthiophene-3-carboxylic acid methyl ester. To 2-[(aminocarbonyl)amino]-5-bromothiophene-3-carboxylic acid methyl ester [prepared according to Example 15] (0.28g, 1.0mmol) , (Ph 3 P) 4 (40 mg, 0.04 mmol) and 4-pyridyl-tributylstannane (0.47 g, 1.2 mmol) in DMF (4.0 mL) were added CuI (40 mg, 0.20 mmol). The resulting homogeneous mixture was heated to 80° C. overnight in a sealed reaction vial with stirring. Cool the reaction to room temperature, filter, and concentrate in vacuo. The residue was subjected to PrepLC (5-80% MeCN, H 2 (2, 0.1% TFA) to give the product as a brown solid (140 mg, 50%).
[0523] 1 H NMR (d 6 -DMSO; 10.25(s, 1H), 8.50(br s, 2H), 7.80(s, 1H), 7.60(d, 2H), 7.30(br s, 2H), 3.85(s, 3H)).LCMS( APCI, M+H=278).
[0524] Benzyl (3S)-3-aminoazepane-1-carboxylate. Dissolve (3S)-azepane-3-amine (12.4 g; 108 mmol) in 200 mL of anhydrous CH ...
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