N-substituted aromatic ring-2-aminopyrimidine compounds and their uses

A technology of aminopyrimidine and compound, which is applied in the field of application of N-substituted aromatic ring-2-aminopyrimidine compounds in the preparation of antitumor drugs, can solve the problems of reducing treatment sensitivity, cell cycle arrest, etc., and achieve good oral administration effect, good protein inhibitory activity, good therapeutic effect

Active Publication Date: 2021-06-04
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, more and more studies in recent years have shown that when DNA is damaged, cell cycle checkpoints are activated, resulting in cell cycle arrest, which facilitates DNA damage repair in cells to maintain the integrity and stability of the genome, and ultimately reduces the efficacy of treatment. sensitivity

Method used

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  • N-substituted aromatic ring-2-aminopyrimidine compounds and their uses
  • N-substituted aromatic ring-2-aminopyrimidine compounds and their uses
  • N-substituted aromatic ring-2-aminopyrimidine compounds and their uses

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0125] Preparation Example 1 5-((4-((piperidin-2-ylmethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanopyridine (Compound 1) synthesis

[0126]

[0127] Step 1. Synthesis of 5-trifluoromethyl-4 chloro-2-aminopyrimidine (Intermediate 1-2)

[0128]

[0129] 2,4-Dichloro-5-trifluoromethylpyrimidine (5.2 g, 24.07 mmol) was dissolved in ammonia-saturated ethanol (25 ml), stirred at room temperature for 2 h, and the solvent was recovered under reduced pressure to obtain a residue, which was filtered through a silica gel column Analytical purification, using PE:EA (5:1) as eluent, gave 1-2 (2.3 g, 11.67 mmol) as a white solid, yield: 48.5%. 1 H NMR (500MHz, CDCl 3 ) δ8.57(s, 1H), 7.98(s, 2H). ESI-MS: m / z=198[M+H] + .

[0130] Step 2.N 4 Synthesis of -(N-tert-butoxycarbonylpiperidin-2-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Intermediate 1-3)

[0131]

[0132] Under ice bath conditions, take intermediate 1-2 (197.0 mg, 1.0 mmol), 1-Boc-2-aminometh...

preparation Embodiment 2

[0136] Preparation Example 2 5-((4-((piperidin-3-ylmethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanopyridine (Compound 2)

[0137]

[0138] Step 1.N 4 Synthesis of -(N-tert-butoxycarbonylpiperidin-3-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Intermediate 1-4)

[0139]

[0140] The synthesis steps refer to step 2 of Example 1. Intermediate 1-4 was synthesized by substituting 1-Boc-3-aminomethylpiperidine for 1-Boc-2-aminomethylpiperidine. Yield: 70%. 1 H NMR (500MHz, CDCl 3 )δ8.08(s, 1H), 5.44(s, 1H), 5.10(s, 2H), 3.85(m, 2H), 3.40(m, 2H), 3.01(m, 1H), 2.88–2.73(m ,1H),1.91–1.81(m,2H),1.77(m,2H),1.68

[0141] (m,1H),1.47(s,9H).ESI-MS: m / z=376[M+H] + .

[0142] Step 2. Synthesis of 5-((4-((piperidin-3-ylmethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanopyridine (compound 2)

[0143]

[0144] Synthesis steps Refer to Example 1, Step 3 to synthesize Compound 2. Yield: 65%. 1 H NMR (500MHz, DMSO) δ 10.30 (s, 1H), 9.07 (d, J=2.5H...

preparation Embodiment 3

[0146] Preparation Example 3 (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanopyridine (Compound 3)

[0147]

[0148] Step 1. (R)-N 4 Synthesis of -(N-tert-butoxycarbonylmorpholin-2-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Intermediate 1-5)

[0149]

[0150] Synthesis steps refer to Example 1, Step 2. Intermediate 1-5 was synthesized by substituting (S)-4-N-Boc-2-aminomethylmorpholine for 1-Boc-2-aminomethylpiperidine. Yield: 65%. 1 H NMR (500MHz, CDCl 3 )δ8.09(s,1H),5.50(s,1H),5.10(s,2H),4.13–3.67(m,4H),3.66–3.49(m,2H),3.47–3.37(m,1H) ,2.96(s,1H),2.69(s,1H),1.49(s,9H).ESI-MS:m / z=378[M+H] + .

[0151] Step 2. (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanopyridine ( Compound 3) Synthesis

[0152]

[0153] Synthesis steps Refer to Example 1, Step 3 to synthesize compound 3. Yield: 70%. 1 H NMR (500MHz, DMSO) δ 10.35(s, 1H), 9.04(d, J=2.0Hz, 1H), 8.50–8.42(m, 1H), 8.31...

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Abstract

The present invention provides an N-substituted aromatic ring-2-aminopyrimidine compound and its use. The compound includes an optical isomer or a pharmaceutically acceptable salt thereof. Experiments have proved that the N-substituted aromatic ring-2-aminopyrimidine compound with a new skeleton of the present invention has good CHK1 protein inhibitory activity, and the compound has obvious in vitro proliferation inhibitory effect on MV4-11, Z138 and other blood tumor cell lines . At the same time, the compound also has a good oral effect. Further in vivo drug efficacy tests have proved that the compound has a good therapeutic effect on human acute myeloid leukemia MV‑4‑11Ba1b / c mouse transplanted tumors, and has a good therapeutic effect on tumors. The synthesis route of the compound of the invention is rationally designed, the required raw materials are readily available, the reaction conditions are mild, the yields of each step are high, the operation is simple and convenient, and the method is suitable for industrialized production. N-substituted aromatic ring-2-aminopyrimidine compounds of the present invention have the following general structural formula:

Description

technical field [0001] The invention relates to the field of medicine, in particular to an N-substituted aromatic ring-2-aminopyrimidine compound and its application as a cell cycle checkpoint kinase 1 (CHK1) inhibitor in the preparation of antitumor drugs. Background technique [0002] DNA damage is one of the main mechanisms of antitumor therapy. Radiation therapy and cytotoxic drugs kill tumors by damaging DNA. However, in recent years, more and more studies have shown that when DNA is damaged, cell cycle checkpoints are activated, resulting in cell cycle arrest, which facilitates DNA damage repair in cells to maintain the integrity and stability of the genome, and ultimately reduces the efficacy of treatment. Sensitivity. [0003] When DNA is damaged to a certain extent by external stimuli such as radiotherapy and cytotoxic drugs, it can cause cell cycle arrest in G1 phase, S phase or G2 / M phase, and then repair damaged DNA. Among them, p53 is mainly responsible for t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D413/14C07D471/08C07D401/12C07D403/04C07D239/48A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D239/48C07D401/12C07D401/14C07D403/04C07D413/14C07D471/08
Inventor 刘滔李佳董晓武周宇波胡永洲王培培金婷婷刘婕妤胡小蓓
Owner ZHEJIANG UNIV
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