2-(4-Morpholino)-4,6-disubstituted pyrimidine/s-triazine compounds, salts thereof, and application of compounds or salts

A disubstituted, morpholino-based technology, applied to 2--4,6-disubstituted pyrimidine or s-triazine compounds and their pharmaceutically acceptable salts and application fields, can solve problems such as poor clinical effects, and achieve anti-inflammatory properties. Good tumor activity

Inactive Publication Date: 2018-02-02
XI AN JIAOTONG UNIV
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AI-Extracted Technical Summary

Problems solved by technology

The vast majority of kinase inhibitors reported in the literature are single-t...
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Method used

[0054] The PI3K/AKT/mTOR signal transduction pathway and the Ras/RAF/MEK/ERK signal tran...
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Abstract

The invention relates to 2-(4-morpholino)-4,6-disubstituted pyrimidine/s-triazine compounds, salts thereof, and an application of the compounds or the salts. The above disclosed 2-(4-morpholino)-4-(N-(1-benzoyl-4-piperidyl)amino)-6-(pyridyl or pyrimidinyl)pyrimidine or s-triazine compounds have a general formula shown in the description; and in the formula, X and Y are N or CH, R<1> is a C1-C3 alkyl group, R<2> is hydrogen, halogen, a methyl group or a trifluoromethyl group, R<3> is an amino group, a methoxy group, a cyano group or a trifluoromethyl group, and X is not N when the R<2> is hydrogen, R<3> is the amino group and Y is N. The compounds and the salts have PI3K and RAF kinase inhibition dual activity, can simultaneously inhibit a PI3K/AKT/mTOR signal transduction pathway and an Ras/RAF/MEK/ERK signal transduction pathway, and have good antitumor activity. The invention also discloses a use of the compounds of the general formula as a PI3K//RAF dual inhibitor.

Application Domain

Organic active ingredientsOrganic chemistry +1

Technology Topic

TrifluoromethylPyrimidine +10

Image

  • 2-(4-Morpholino)-4,6-disubstituted pyrimidine/s-triazine compounds, salts thereof, and application of compounds or salts
  • 2-(4-Morpholino)-4,6-disubstituted pyrimidine/s-triazine compounds, salts thereof, and application of compounds or salts
  • 2-(4-Morpholino)-4,6-disubstituted pyrimidine/s-triazine compounds, salts thereof, and application of compounds or salts

Examples

  • Experimental program(20)

Example Embodiment

[0033] The 2-(4-morpholinyl)-4-(N-alkyl-N-(1-benzoyl-4-piperidinyl)amino)-6-(pyridinyl or pyrimidinyl)pyrimidine or The synthesis method of s-triazine compounds includes the following three steps:
[0034] Step 1: In the presence of alkaline reagents, 2,4,6-trichloropyrimidine or 2,4,6-trichloro-1,3,5-triazine and 4-substituted amino-1-benzoylpiperidine Intermediate M is obtained through nucleophilic substitution reaction in organic solvent;
[0035] Step 2: 2,6-Dichloro-4-(N-alkyl-N-(1-benzoyl-4-piperidinyl)amino)-1,3,5-triazine or 2,6-di Chloro-4-(N-alkyl-N-(1-benzoyl-4-piperidinyl)amino)pyrimidine reacts with morpholine in an organic solvent to obtain intermediate N;
[0036] Step 3: Under the catalysis of palladium complex, intermediate N and substituted 3-pyrimidinyl boronic acid ester or substituted 5-pyrimidinyl boronic acid ester undergo Suzuki coupling to obtain product P.
[0037] The synthetic route is as follows:
[0038]
[0039] Wherein, the alkaline reagent is triethylamine, diisopropylethylamine, DBU, pyridine or potassium carbonate, cesium carbonate; the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethyl Base formamide; the palladium complex is PdCl 2 (dppf), Pd(PPh 3 ) 4 Wait.
[0040] 2-(4-morpholinyl)-4-(N-alkyl-N-(1-benzoyl-4-piperidinyl)amino)-6-(pyridyl or pyrimidinyl) pyrimidine or triazine The pharmaceutically acceptable salt of the compound has the following structure:
[0041]
[0042] Among them, HZ stands for acid.
[0043] The pharmaceutically acceptable salts are hydrochloride, hydrobromide, nitrate, phosphate, sulfate, acetate, fumarate, malate, citrate, tartrate, maleate, Lactate, citrate, camphorsulfonate, benzoate, gluconate, glutamate, isethionate, succinate, besylate, or methanesulfonate.
[0044] 2-(4-morpholinyl)-4-(N-alkyl-N-(1-benzoyl-4-piperidinyl)amino)-6-(pyridyl or pyrimidinyl) pyrimidine or triazine The compound and the acid are stirred in an organic solvent to obtain their salts.
[0045] 2-(4-morpholinyl)-4-(N-(1-benzoyl-4-piperidinyl)amino)-6-(pyridyl or pyrimidinyl) pyrimidine (or triazine) compound or The use of pharmaceutically acceptable salts in the preparation of anti-tumor drug preparations.
[0046] Wherein, the anti-tumor drug preparation is a drug preparation capable of inhibiting PI3K or RAF. Furthermore, PI3K mainly refers to PI3Kα; RAF refers to BRAF.
[0047] Wherein, the anti-tumor drug preparation can be used for the treatment of cancers with high expression or mutation of PI3K or RAF.
[0048] Among them, the 2-(4-morpholinyl)-4,6-disubstituted pyrimidine (or s-triazine) compound or 2-(4-morpholinyl)-4,6-disubstituted pyrimidine described in the present invention The pharmaceutically acceptable salts of (or s-triazine) compounds can be combined with other types of anti-tumor drugs, such as anti-tumor drugs that directly act on DNA, antimetabolites and anti-tumor drugs, anti-mitotic drugs and EGFR inhibitors, BTK inhibitors, etc. The composition of the drug complex obtains a better anti-tumor effect.
[0049] The anti-tumor drug preparation is a tablet, a capsule or an injection, wherein each tablet, granule or each preparation contains 30-500 mg of 2-(4-morpholinyl)-4-(N-alkyl-N -(1-Benzoyl-4-piperidinyl)amino)-6-(pyridyl or pyrimidinyl)pyrimidine (or triazine) compound or a pharmaceutically acceptable salt thereof.
[0050] Preferably, the anti-tumor drug preparation is a tablet or capsule, and each tablet or capsule contains 50-300 mg of 2-(4-morpholinyl)-4-(N-alkyl-N- (1-Benzoyl-4-piperidinyl)amino)-6-(pyridyl or pyrimidinyl)pyrimidine (or s-triazine) compound or a pharmaceutically acceptable salt thereof.
[0051] Further, the anti-tumor drug preparation also includes auxiliary materials, which include one or more of stabilizers, solubilizers, lubricants and disintegrants. Further preferably, the auxiliary materials include starch, dextrin, glucose, lactose, cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, pectin, cyclodextrin, Tween-80, polyvinyl alcohol, magnesium stearate and talc One or more of powder.
[0052] Compared with the prior art, the present invention provides 2-(4-morpholinyl)-4-(N-alkyl-N-(1-benzoyl-4-piperidinyl)amino)-6-( Pyridyl or pyrimidinyl) pyrimidine (or s-triazine) compounds and their salts have the following beneficial effects:
[0053] The compounds and their salts provided by the present invention have the dual activity of inhibiting PI3K and RAF kinases,
[0054] It can simultaneously inhibit PI3K/AKT/mTOR signal transduction pathway and Ras/RAF/MEK/ERK signal transduction pathway, and has better anti-tumor activity.
[0055] The compounds and their salts provided by the invention have strong activity. The anti-proliferation activity of this class of compounds on a variety of human cancer cells, such as human colon cancer cell HCT116, human lung cancer cell A549, human melanoma cell A375, etc., is stronger or close to the positive drug VS-5584 or Verofinil.
[0056] The compound provided by the invention has a simple synthetic route, easily obtained synthetic raw materials, and easy realization of the synthetic method.
[0057] 2-(4-morpholinyl)-4-(N-alkyl-N-(1-benzoyl-4-piperidinyl)amino)-6-(pyridyl or pyrimidinyl)pyrimidine provided by the invention (Or s-triazine) compounds and their salts can be used to prepare anti-tumor drug preparations, which can provide more options for the clinical treatment of cancer.
[0058] The following further illustrates the present invention through the synthesis process and efficacy of some representative compounds of the present invention. The numbers and structural formulas of the representative compounds are as follows:
[0059]

Example Embodiment

[0061] Example 1: 2-(4-morpholinyl)-4-(2-amino-5-pyrimidinyl)-6-(N-cyclopropyl-N-(1-(3-fluorobenzoyl)- Synthesis of 4-piperidinyl))amino-1,3,5-triazine (compound 1)
[0062] step one:
[0063]
[0064] Add acetone (15mL) and 2,4,6-trichloro-1,3,5-triazine (0.61g) into a round bottom flask, cool to -10°C, and add 4-cyclopropylamino-1-( A mixture of 3-fluorobenzoyl)piperidine (0.90 g), triethylamine (TEA, 0.46 mL) and acetone (15 mL). After the addition was completed in about 30 minutes, the acetone was removed under reduced pressure, water (10 mL) was added to the residue, and extraction was performed twice with dichloromethane (20 mL). The extract was dried with anhydrous sodium sulfate and the solvent was removed to obtain intermediate M1 (oil).
[0065] Step two:
[0066]
[0067] Intermediate M1, morpholine, diisopropylethylamine and dichloromethane were added to a round bottom flask, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was directly mixed with silica gel and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) to obtain intermediate N1. The two-step yield is about 70%.
[0068] Step three:
[0069]
[0070] To the dioxane solution of 2-amino-4-pyrimidinylboronic acid pinacol ester, add intermediate N1, potassium carbonate, and PdCl in turn 2 (dppf), water, the mixture was heated to reflux for 6 hours, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain compound 1 (light yellow solid, yield 71%). EI-MS: 520 (M+H).

Example Embodiment

[0071] Example 2: 2-(4-morpholinyl)-4-(2-amino-5-pyrimidinyl)-6-(N-cyclopropyl-N-(1-(3-methylbenzoyl) -4-piperidinyl)) amino-1,3,5-triazine (compound 2) synthesis
[0072] Same as the synthesis of compound 1. Replace 4-cyclopropylamino-1-(3-fluorobenzoyl)piperidine with 4-cyclopropylamino-1-(3-methylbenzoyl)piperidine. The total yield of the three steps is 44%. EI-MS: 516 (M+H).

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