N-subsituted aromatic ring-2-amino pyrimidine compound and applications

An aminopyrimidine and compound technology, applied in the direction of organic chemistry, drug combination, antitumor drugs, etc., can solve the problems of reducing the sensitivity of treatment, cell cycle arrest, etc., and achieve the effect of good therapeutic effect

Active Publication Date: 2020-03-10
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, w...

Method used

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  • N-subsituted aromatic ring-2-amino pyrimidine compound and applications
  • N-subsituted aromatic ring-2-amino pyrimidine compound and applications
  • N-subsituted aromatic ring-2-amino pyrimidine compound and applications

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] Dissolve 2,4-dichloro-5-trifluoromethylpyrimidine (5.2g, 24.07mmol) in ammonia-saturated ethanol (25ml), stir at room temperature for 2h, recover the solvent under reduced pressure to obtain a residue, and use silica gel column layer Analysis and purification, using PE:EA (5:1) as the eluent, gave white solid 1-2 (2.3g, 11.67mmol), 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 condition, take intermediate 1-2 (197.0mg, 1.0mmol), 1-Boc-2-aminomethylpiperidine (256.8mg, 1.2mmol), dissolve in m...

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] For the synthesis steps, refer to Step 2 of Example 1. Intermediate 1-4 was synthesized by replacing 1-Boc-2-aminomethylpiperidine with 1-Boc-3-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 step 3 of Example 1 to synthesize compound 2. Yield: 65%. 1 H NMR(500MHz,DMSO)δ10.30(s,1H),9.07(d,J=2.5Hz,1H),8.42(dd,J=9...

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] For the synthesis steps, refer to Step 2 of Example 1. Intermediate 1-5 was synthesized by replacing 1-Boc-2-aminomethylpiperidine with (S)-4-N-Boc-2-aminomethylmorpholine. 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 Referring to Step 3 of Example 1, compound 3 was synthesized. Yield: 70%. 1 H NMR (500MHz, DMSO) δ10.35(s, 1H), 9.04(d, J=2.0Hz, 1H), 8.50–...

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Abstract

The invention provides an N-subsituted aromatic ring-2-amino pyrimidine compound and applications. The compound includes an optical isomer or a pharmaceutically acceptable salt. A test proves that theN-subsituted aromatic ring-2-amino pyrimidine having a novel framework has excellent CHK1 protein inhibition activity and has significant in-vitro proliferation inhibition effect on MV4-11, Z138 andthe like blood tumor cell strains; meanwhile, the compound also has excellent oral delivery effect. Further in-vivo efficacy test proves that the compound has great treatment effect on human acute myelogenous leukemia MV-4-11 Ba1b/c mouse transplantation tumor and has great treatment effect on tumor. The compound is reasonable in synthesis route design, is prepared from feasible raw materials andgentle reaction conditions, is high in yield in every step and is simple in preparation operation, and is suitable in industrial production. The N-subsituted aromatic ring-2-amino pyrimidine compoundhas a structural general formula as the specification.

Description

technical field [0001] The invention relates to the field of medicines, in particular to an N-substituted aromatic ring-2-aminopyrimidine compound and its use 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, 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. [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 the damaged DNA. Among them, p53 is mainly responsible for the r...

Claims

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Application Information

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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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